An Overview On Synthetic 2-Aminothiazole-Based Compounds Associated With Four Biological Activities

4.6 6.
Review
An Overview on Synthetic 2-
Aminothiazole-Based Compounds
Associated with Four Biological
Activities
Mohamed Farouk Elsadek, Badreldin Mohamed Ahmed and Mohamed Fawzi Farahat
https://doi.org/10.3390/molecules26051449
molecules
Review
An Overview on Synthetic 2-Aminothiazole-Based Compounds
Associated with Four Biological Activities
Mohamed Farouk Elsadek 1,2, * , Badreldin Mohamed Ahmed 1 and Mohamed Fawzi Farahat 1
1 Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University,
P.O. Box 10219, Riyadh 11433, Saudi Arabia; bmohamed@ksu.edu.sa (B.M.A.); mffarahat@ksu.edu.sa (M.F.F.)
2 Nutrition and Food Science Department, Faculty of Home Economics, Helwan University, P.O. Box 11795,
Cairo 11511, Egypt
* Correspondence: mfbadr@ksu.edu.sa; Tel.: +966-01-4693681
Abstract: Amongst sulfur- and nitrogen-containing heterocyclic compounds, the 2-aminothiazole

scaffold is one of the characteristic structures in drug development as this essential revelation has
several biological activities abiding it to act as an anticancer, antioxidant, antimicrobial and anti-
inflammatory agent, among other things. Additionally, various 2-aminothiazole-based derivatives as
medical drugs have been broadly used to remedy different kinds of diseases with high therapeutic
influence, which has led to their wide innovations. Owing to their wide scale of biological activities,
their structural variations have produced attention amongst medicinal chemists. The present review
highlights the recently synthesized 2-aminothiazole-containing compounds in the last thirteen years
(2008–2020). The originality of this proposal is based on the synthetic strategies developed to
access the novel 2-aminothiazole derivatives (N-substituted, 3-substituted, 4-substituted, multi-
Citation: Farouk Elsadek, M.; substituted, aryl/alkyl substituents or acyl/other substituents). The literature reports many synthetic
Mohamed Ahmed, B.; Fawzi Farahat, pathways of these 2-aminothiazoles associated with four different biological activities (anticancer,
M. An Overview on Synthetic antioxidant, antimicrobial and anti-inflammatory activities). It is wished that this review will be
2-Aminothiazole-Based Compounds accommodating for new views in the expedition for rationalistic designs of 2-aminothiazole-based
Associated with Four Biological medical synthetic pathways.
Activities. Molecules 2021, 26, 1449.
https://doi.org/10.3390/ Keywords: 2-aminothiazoles; antibacterial; anti-inflammatory
molecules26051449
Academic Editors: Ari Koskinen and

Gianfranco Favi
1. Introduction
Received: 2 December 2020 Heterocyclic compounds are so important due to their versatile applications. A large
Accepted: 3 March 2021 number of heterocyclic compounds containing nitrogen and sulfur are used as medicine
Published: 7 March 2021 in different therapeutic targets. Thiazole is one of the important pharmacophores in drug
discovery and development processes. There are many substituted thiazole-containing
Publisher’s Note: MDPI stays neutral heterocycles covering a wide range of therapeutic targets including antimicrobial, anti-
with regard to jurisdictional claims in cancer, anti-inflammatory and anti-HIV. Aminothiazole scaffolds are important structural
published maps and institutional affil- units in medicinal chemistry as they have shown antitumor [1–3], antiviral [4–6], antibac-
iations. terial [7–9], anti-prion [10], psychotropic [11], anti-allergic [12], anti-hypertensive [13],
anti-inflammatory [14,15], antifungal [16], antitubercular [17,18], anti-HIV [19], pestici-
dal [20], antiprotozoal [21], antipyretic [22], antioxidative [23] and analgesic activities [24].
Aminothiazole compounds act as ligands of estrogen receptors [25] and afford a new group
Copyright: © 2021 by the authors. of adenosine receptor antagonists [26]. They are also utilized as fungicides, inhibiting the
Licensee MDPI, Basel, Switzerland. in vivo growth of Xanthomonas, or as schistosomicidal and anthelmintic drugs [27].
This article is an open access article
distributed under the terms and
2. Results
conditions of the Creative Commons 2.1. 2-Aminothiazoles as Anticancer Agents
Attribution (CC BY) license (https:// Clinical administration of high doses of anticancer drugs to defeat resistance leads to
creativecommons.org/licenses/by/ severe toxicities [28]. The literature survey revealed that heterocyclic thiazole derivatives
4.0/).
Molecules 2021, 26, 1449. https://doi.org/10.3390/molecules26051449 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, x FOR PEER REVIEW 2 of 42
Molecules 2021, 26, 1449 Clinical administration of high doses of anticancer drugs to defeat resistance 2 ofleads
37 to
severe toxicities [28]. The literature survey revealed that heterocyclic thiazole derivatives
were integrated with other moieties to evaluate their anticancer effect. The synthetic
protocol of paeonol-2-aminothiazole-phenylsulfonyl
were integrated derivatives
with other moieties to evaluate their anticancer 4 involved
effect. The synthetic pro-treating
paeonol
tocol of(1) with thiourea and iodine in refluxing
paeonol-2-aminothiazole-phenylsulfonyl ethyl 4alcohol
derivatives involvedtotreating
furnish the corre-
paeonol
(1) with2-aminothiazole
sponding thiourea and iodine in refluxing
scaffold ethyl
2, which wasalcohol to furnish
treated the corresponding
with phenylsulfonyl 2-
chloride 3
aminothiazole scaffold 2, which was treated with phenylsulfonyl chloride 3 that had been
that had been substituted to produce the final wanted compound 4 (Scheme 1). The cy-
substituted to produce the final wanted compound 4 (Scheme 1). The cytotoxic effects
totoxic effects of various paeonol-2-aminothiazole-phenylsulfonyl derivatives 4 were
of various paeonol-2-aminothiazole-phenylsulfonyl derivatives 4 were assessed against
assessed against
fibroblast fibroblast cells
cells (BALB/3T3) (BALB/3T3)
and seven andlines.
cancer cell seven
Thecancer cell lines.
F and OCH The F and OCH3
3 derivatives of the
derivatives of the thiazole-paeonolphenylsulfonyl
thiazole-paeonolphenylsulfonyl scaffold
scaffold showed cytotoxic potentshowed cytotoxic
effects against potent ef-
the tested
fects against the tested
cancer cell lines [29]. cancer cell lines [29].
Scheme 1. Synthesis
Scheme of various
1. Synthesis ofpaeonol-2-aminothiazole-phenylsulfonyl derivatives 4. derivatives 4.
various paeonol-2-aminothiazole-phenylsulfonyl
New cinnamic acid amide scaffolds 9 comprising thiazoles were designed and syn-
New cinnamic
thesized as outlinedacid amide 2.
in Scheme scaffolds 9 comprising
The results of anticancerthiazoles
activity ofwere designed
this work and syn-
indicated
thesized as outlined
that compound 9 (Rin =Scheme
1 R = H,2.
2 R The
3 results of
= OCOMe) anticancer
features activity
potential of this work
characteristics indicated
for drug
thatdevelopment
compoundcombining
9 (R1 = R2both= H,coagulant
R3 = OCOMe) features potential
and platelet effects [30]. characteristics for drug
development combining
The thiazole both10coagulant
derivative and by
was produced platelet
heatingeffects [30].bromide with thiourea
phenacyl
in ethyl alcohol, which acetylated by acetic anhydride to furnish the corresponding N-
acetyl compound 11. The nucleophilic addition of 10 to phenyl isothiocyanate afforded the
N-phenylthiourea derivative 12. In contrast, the reaction of 10 with ethyl cyanoacetate in
dimethyl formamide produced N-cyanoacetamide derivative 13. Condensation of 13 with
three types of substituted benzaldehydes (namely, benzaldehyde 4-chlorobenzaldehyde
or 4-methoxybenzaldehyde) produced the corresponding benzylidene derivatives 14. In
addition, when compound 13 reacted with salicylaldehyde, it gave the coumarin derivative
15 (Scheme 3) [31].
The reaction of acetamide derivative 13 with various aryl diazonium chlorides af-
fords the aryl hydrazone compounds 16. In addition, the multi-component reaction of
13 with substituted benzaldehydes and malononitrile produced the pyran derivatives 17
(Scheme 4). Compound 13 was applied for thiazole synthesis, and as a result, compound
13 reacted with elemental sulfur and phenyl isothiocyanate to afford the thiazole derivative
18. Similarly, the multi-component reaction of 13 with substituted benzaldehydes and
ethyl cyanoacetate produced the pyran derivatives 19a–c (Scheme 4). Furthermore, the
multi-component reaction of 13 with substituted benzaldehydes and thiourea produced the
pyrimidine scaffolds 20. 2-Amino-4-(4-chlorophenyl)-6-(4-phenylthiazol-2-yl)-4H-pyran-
Molecules 2021, 26, 1449 3 of 37

3,5-dicarbonitrile (17, X = Cl) indicated the maximum cytotoxicity among the synthesized
compounds towards six cancer cell lines [31].

Scheme 2. Synthesis
2. Synthesis
Scheme of cinnamic
of cinnamic acid amide
acid amide scaffolds
scaffolds 9. 9.
The thiazole derivative 10 was produced by heating phenacyl bromide with thiourea
in ethyl alcohol, which acetylated by acetic anhydride to furnish the corresponding
N-acetyl compound 11. The nucleophilic addition of 10 to phenyl isothiocyanate afforded
the N-phenylthiourea derivative 12. In contrast, the reaction of 10 with ethyl cyanoacetate
in dimethyl formamide produced N-cyanoacetamide derivative 13. Condensation of 13
with three types of substituted benzaldehydes (namely, benzaldehyde
4-chlorobenzaldehyde or 4-methoxybenzaldehyde) produced the corresponding ben-
zylidene derivatives 14. In addition, when compound 13 reacted with salicylaldehyde, it
gave the coumarin derivative 15 (Scheme 3) [31].
Scheme 3. Scheme
Synthesis
3. of coumarin
Synthesis derivative
of coumarin 15.
derivative 15.
The reaction of acetamide derivative 13 with various aryl diazonium chlorides af-
fords the aryl hydrazone compounds 16. In addition, the multi-component reaction of 13
with substituted benzaldehydes and malononitrile produced the pyran derivatives 17
(Scheme 4). Compound 13 was applied for thiazole synthesis, and as a result, compound
Molecules 2021,
Molecules 26,26,
2021, 1449 PEER REVIEW
x FOR 4 of537of 42
Scheme 4.Scheme 4. Synthesis

Synthesis of pyran of pyran derivatives
derivatives 19a–c. 19a–c.
Treatment of 3-ethoxyacryloyl chloride with either 2-methylaniline or 2-chloro-6-

Treatment of 3-ethoxyacryloyl chloride with either 2-methylaniline or
methylaniline in tetrahydrofuran utilizing basic pyridine as a catalyst gave the substituted
2-chloro-6-methylaniline in tetrahydrofuran utilizing basic pyridine as a catalyst gave the
3-ethoxyacrylamides 21, and then treatment of 21 with N-bromosuccinimide produced the
substituted 3-ethoxyacrylamides 21, and then treatment of 21 with N-bromosuccinimide
crude α-formyl-α-bromoacetate hemiacetals 22. Addition of thiourea to hemiacetals 22 gave
produced the crude α-formyl-α-bromoacetate
the 2-amino-thiazole-5-carboxylic hemiacetals
acid phenylamides 23, which22. Addition
reacted of thiourea to
with chloroacetyl
hemiacetals 22 gave
chloride in the the 2-amino-thiazole-5-carboxylic
presence of K2 CO3 as a base to afford theacidkeyphenylamides 23, Finally,
intermediates 24. which re-
acted with chloroacetyl chloride in the presence of K 2 CO 3 as a base to afford
chloroacetamide derivatives 24 reacted with various secondary amine compounds to afford the key in-
termediates 24. Finally, chloroacetamide derivatives 24 reacted with various
the final products 25 (Scheme 5). The synthesized series of 2-amino-thiazole-5-carboxylic secondary
amine compounds to
acid phenylamide afford theshowed
derivatives final products 25 (Scheme 5). effects
good anti-proliferative The synthesized
on human series
K563 of
2-amino-thiazole-5-carboxylic
leukemia cells [32]. acid phenylamide derivatives showed good an-
ti-proliferative
Accordingeffects on human K563
to the significance of theleukemia cellsside
carboxanilide [32].
chain on the fifth position of the
thiazole ring and the cytostatic impact on human chronic myeloid leukemia cell line K562,
2-aminothiazole-5-carbamides 28 were synthesized as outlined in Scheme 6. 3-Ethoxy-N-
arylpropenamides 26 were synthesized by nucleophilic substitution of suitable aniline onto
3-ethoxyacryloyl chloride. Reaction of the advanced enones 26 with N-bromosuccinimide
(NBS) followed by a coupling of thiourea installed thiazole ring 27. The last step was a
nucleophilic displacement of acetic anhydride or various benzoyl chlorides to give the
corresponding target 28 derivatives [33].
Molecules 2021, 26, 1449 5 of 37

Scheme
Scheme 5. 5. Synthesis
Synthesis of 2-amino-thiazole-5-carboxylic
of 2-amino-thiazole-5-carboxylic acid phenylamide
acid phenylamide derivatives.
derivatives.
According to the significance of the carboxanilide side chain on the fifth position of
the thiazole ring and the cytostatic impact on human chronic myeloid leukemia cell line
K562, 2-aminothiazole-5-carbamides 28 were synthesized as outlined in Scheme 6.
3-Ethoxy-N-arylpropenamides 26 were synthesized by nucleophilic substitution of suit-
able aniline onto 3-ethoxyacryloyl chloride. Reaction of the advanced enones 26 with
N-bromosuccinimide (NBS) followed by a coupling of thiourea installed thiazole ring 27.
The last step was a nucleophilic displacement of acetic anhydride or various benzoyl
chlorides to give the corresponding target 28 derivatives [33].
Scheme 6. Synthesis
Scheme of 2-aminothiazole-5-carbamides
6. Synthesis 28. 28.
of 2-aminothiazole-5-carbamides
The synthesis of N-(5-(4-fluorophenyl)thiazol-2-yl)-3-(furan-2-yl)propanamide (31)

as outlined in Scheme 7 involves the reaction of 2-amino-5-bromothiazole (29) with
3-(furan-2-yl)propanoic acid followed by the Suzuki reaction of the amide product 30
with 4-fluorophenylboric acid. Compound 31 affords the potent inhibitory effect on
Molecules 2021, 26, 1449 6 of 37
Scheme 6. Synthesis of 2-aminothiazole-5-carbamides 28.
The
The synthesis
synthesis of N-(5-(4-fluorophenyl)thiazol-2-yl)-3-(furan-2-yl)propanamide (31)
of N-(5-(4-fluorophenyl)thiazol-2-yl)-3-(furan-2-yl)propanamide (31)
as
as outlined in Scheme
outlined in Scheme 77 involves
involvesthe
thereaction
reactionofof2-amino-5-bromothiazole
2-amino-5-bromothiazole(29) (29)with
with3-
3-(furan-2-yl)propanoic
(furan-2-yl)propanoic acid acid followed
followed byby
thethe Suzuki
Suzuki reaction
reaction of amide
of the the amide product
product 30
30 with
with 4-fluorophenylboric
4-fluorophenylboric acid. Compound
acid. Compound 31 the
31 affords affords
potentthe potent effect
inhibitory inhibitory effect and
on KPNB1 on
KPNB1 and anticancer activity in cell-based assays [34].
anticancer activity in cell-based assays [34].
Synthesis
Scheme 7.Scheme of N-(5-(4-fluorophenyl)thiazol-2-yl)-3-(furan-2-yl)
7. Synthesis propanamide.
of N-(5-(4-fluorophenyl)thiazol-2-yl)-3-(furan-2-yl) propanamide.
The synthesis
The synthesisofof4,5-substituted-2-aminothiazoles
4,5-substituted-2-aminothiazoles 10 and
10 32
and(Scheme 8) has been
32 (Scheme achieved
8) has been
according to the literature by the reaction of acetophenone or cyclohexanone
achieved according to the literature by the reaction of acetophenone or cyclohexanone with thiourea
in thethiourea
with presenceinofthe
iodine. Compound
presence or 32 was stirred
10 Compound
of iodine. 10 orwith
32 was acidstirred
and/or acylacid
with chloride
and/orto
afford the corresponding amide compounds 34 (R 1 = -CH CH COOEt, 4-pyridyl, styryl and
acyl chloride to afford the corresponding amide compounds 34 (R = -CH2CH2COOEt,
2 2 1
3,5-dimethoxystyryl)
4-pyridyl, styryl and 35 (R1 = -CH2 CH2 COOEt
and 3,5-dimethoxystyryl) andand353,5-dimethoxystyryl),
(R1 = -CH2CH2COOEt respectively.
and
Compound 4-(2,4-diethoxyphenyl)thiazol-2-amine (33) was reacted with 1H-indole-3- carbox-
3,5-dimethoxystyryl),
Molecules 2021, 26, x FOR PEER REVIEW respectively. Compound 4-(2,4-diethoxyphenyl)thiazol-2-amine
aldehyde in ethyl alcohol to afford the Schiff base compound 36 [35]. Derivatives 32–368were of 42
(33) was reacted with 1H-indole-3- carboxaldehyde in ethyl alcohol to afford the Schiff
exhibited as potent Poly(ADP-Ribose) Polymerase-1 inhibitors.
base compound 36 [35]. Derivatives 32–36 were exhibited as potent Poly(ADP-Ribose)
Polymerase-1 inhibitors.
Scheme
Scheme8.8.Synthesis
Synthesisofof
4,5-substituted-2-aminothiazoles
4,5-substituted-2-aminothiazoles32–36.
32–36.
Benzimidazole-thiazole derivatives were prepared by heating a mixture of equimo-

lar amounts of 2-acetylbenzimidazoles and thiourea in ethyl alcohol and an excess
amount of iodine [36]. The acid anhydride effect on compound 37a was studied (Scheme
Molecules 2021, 26, 1449 7 of 37
Benzimidazole-thiazole derivatives were prepared by heating a mixture of equimolar

amounts of 2-acetylbenzimidazoles and thiourea in ethyl alcohol and an excess amount of
iodine [36]. The acid anhydride effect on compound 37a was studied (Scheme 9) which
was condensed with various acid anhydrides (namely, succinic anhydride, phthalic anhy-
dride, dichloromalic anhydride and/or tetrabromophthalic anhydride) in acetic acid to
produce the wanted anhydride compounds 38a–d [37]. It is known that an aromatic amino
group substitution is workable by its diazonium salt preparation and subsequent replace-
ment with a nucleophile via Sandmeyer reactions. Therefore, compound 37a was reacted
with CuSO4 , NaNO2 and NaCl to afford the corresponding 2-chlorothiazole scaffold 39.
Meanwhile, 37a was condensed via different acid anhydrides to give the corresponding
derivatives 38a–d. In contrast, compound 37b was reacted with malononitrile in acetic acid
to produce 5-amino-pyrimidine derivative 40 [37]. The compound 37b was acylated with
chloroacetyl chloride to give the corresponding chloroacetamide compound 41 (Scheme 9).
All of these synthesized derivatives showed respectable anticancer activities toward HepG2
and PC12 cell lines.
Scheme 9. Synthesis
Scheme of
9. derivatives
Synthesis of 38–41.
derivatives 38–41.
Meanwhile,Schiff’s
Meanwhile, Schiff’s bases
bases are
are deemed
deemedsignificant
significantintermediates
intermediatesforfor
thethe
synthesis of of
synthesis
other heterocycles. Consequently, Schiff’s bases 42a–c were constructed by the
other heterocycles. Consequently, Schiff’s bases 42a–c were constructed by the reaction of reaction
of 37a
37a withdifferent
with different substituted
substituted benzaldehydes, namely,
benzaldehydes, 4-methoxybenzaldehyde,
namely, 3,4,5-
4-methoxybenzaldehyde,
trimethoxybezaldehye and/or 4-fluorobenzaldehyde in ethanol to produce N-(substituted)-
3,4,5-trimethoxybezaldehye and/or 4-fluorobenzaldehyde in ethanol to produce
thiazol-2-amine 42a–c, respectively. A set of compounds comprising thiazolidinone and
N-(substituted)-thiazol-2-amine 42a–c, respectively. A set of compounds comprising
benzothiazine nuclei were accomplished by cyclizing Schiff’s base 42c by either thiosali-
thiazolidinone and benzothiazine nuclei were accomplished by cyclizing Schiff’s base 42c
cylic acid and/or thioglycolic acid to get thiazolidinone and benzothiazinone 43 and 44
byderivatives,
either thiosalicylic acid
respectively and/or
[37] (Schemethioglycolic acid tocompounds
10). Meanwhile, get thiazolidinone
43 showed and benzothia-
promising
zinone 43 and 44 derivatives, respectively [37] (Scheme
anticancer activity against both of HepG2 and PC12 cell lines. 10). Meanwhile, compounds 43
showed promising anticancer activity against both of HepG2 and PC12 cell lines.
Molecules 2021, 26, 1449 8 of 37
Scheme 10. Scheme

Synthesis10.
ofSynthesis
derivatives
of 42–44.
Additionally, aminothiazole
Additionally, aminothiazole derivative
derivative 41 was cyclized
41 was cyclized with
with 1,2-ethylenediamine
1,2-ethylenediamine
and/or ortho-substituted aniline compounds to give the corresponding 2-amino-pyrazine
and/or ortho-substituted aniline compounds to give the corresponding 2-amino-pyrazine
45 and 46a–c, respectively. In contrast, compound 41 was cyclized with
45 and 46a–c, respectively. In contrast, compound 41 was cyclized with HS-CH HS-CH 2 -COOH
2-COOH
to
produce thiazinedione scaffold 47. Furthermore, compound 41 was cyclized
to produce thiazinedione scaffold 47. Furthermore, compound 41 was cyclized with with various
semicarbazide
various or thiosemicarbazide
semicarbazide derivatives
or thiosemicarbazide to afford to
derivatives 1,3,4-oxadiazine 48a and 1,3,4-
afford 1,3,4-oxadiazine 48a
thiadiazine 48b–d compounds [37] (Scheme 11). Among these derivatives,
and 1,3,4-thiadiazine 48b–d compounds [37] (Scheme 11). Among these derivatives, 48c 48c showed
high activity
showed high against
activity the PC12the
against anticancer cell line.cell line.
PC12 anticancer
Compound 41 containing an aminothiazole moiety was heated with malononitrile
in sodium ethoxide to give the corresponding 3-cyano-5-oxo-1H-pyrrole derivative 49. In
addition, treatment of compound 41 with different secondary amines gave the acetamide
derivatives 50a–c. Moreover, treatment of 41 with potassium thiocyanate produced the
thiocyanate-acetamide scaffold 51, which was cyclized to yield the corresponding thiazo-
lidinone 52 (Scheme 12). The prepared compounds have potent anticancer activity against
PC12 and HepG2 cell lines [37].
Heterocyclization of 2-aminothiazole 8 with α-bromo-3-methoxyacetophenone pro-
ceeded by heating in ethyl alcohol to yield 6-(3-methoxyphenyl)imidazo[2,1-b]thiazole 53,
which underwent heating with 4-iodo-2-(methylthio)pyrimidine in the presence of palla-
dium acetate, cesium carbonate and triphenyl phosphine to give the corresponding methyl
thiopyrimidinyl compound 54 (Scheme 13). The sulfide moiety of 54 was oxidized by oxone
to produce the corresponding sulfonyl compound 55 [38]. The derivatives 53–55 were
utilized as precursors for the synthesis of compounds 58–61 that displayed a remarkable
activity toward the A375P human melanoma cell line (HepG2).
Molecules 2021, 26, 1449 9 of 37

Scheme 11.Scheme
Synthesis
11.ofSynthesis
of derivatives 45–48.
Compound 41 containing an aminothiazole moiety was heated with malononitrile in

sodium ethoxide to give the corresponding 3-cyano-5-oxo-1H-pyrrole derivative 49. In
addition, treatment of compound 41 with different secondary amines gave the acetamide
derivatives 50a–c. Moreover, treatment of 41 with potassium thiocyanate produced the
thiocyanate-acetamide scaffold 51, which was cyclized to yield the corresponding thia-
zolidinone 52 (Scheme 12). The prepared compounds have potent anticancer activity
against PC12 and HepG2 cell lines [37].
Scheme 12.Scheme
Synthesis
12.ofSynthesis
derivatives
of 49–52.
Heterocyclization of 2-aminothiazole 8 with α-bromo-3-methoxyacetophenone

proceeded by heating in ethyl alcohol to yield
6-(3-methoxyphenyl)imidazo[2,1-b]thiazole 53, which underwent heating with
4-iodo-2-(methylthio)pyrimidine in the presence of palladium acetate, cesium carbonate
Molecules 2021, 26, 1449 10 of 37
Scheme 13. Scheme

Synthesis
13.ofSynthesis
Heating of
Heating ofthe
thesulfone-containing
sulfone-containing thiazolyl moiety
thiazolyl compound
moiety compound55 with55the ureathe
with and/or
urea
amide reagents and in the presence of DIPEA (N,N-Diisopropyl ethyl
and/or amide reagents 56 and 57 in the presence of DIPEA (N,N-Diisopropyl ethyl amine)
56 57 amine) gave the
target methoxy compounds and respectively. Demethylation of
gave the target methoxy compounds 58 and 59, respectively. Demethylation of the
58 59, the methoxy group of
and using boron tribromide produced the corresponding hydroxyl
methoxy group of 58 and 59 using boron tribromide produced the corresponding hy-
58 59 target compounds
60a–c and
droxyl 61a–c,
target respectively
compounds (Scheme
60a–c 14) [38].
and 61a–c, The prepared
respectively derivatives
(Scheme 58b,The
14) [38]. 58c,prepared
60b, 59b,
61a and 61b showed superior potency against the A375P “human melanoma
derivatives 58b, 58c, 60b, 59b, 61a and 61b showed superior potency against the A375P cell line” than
sorafenib. Moreover, derivatives 61a and 61b revealed the highest potency
“human melanoma cell line” than sorafenib. Moreover, derivatives 61a and 61b revealed (IC50 = 0.5 and
2.1 µM, respectively). Derivatives with m-hydroxyphenyl on the
the highest potency (IC50 = 0.5 and 2.1 µM, respectively). Derivatives withimidazothiazole moiety
such as 60b, 61a and
m-hydroxyphenyl on61btheshowed greater potency
imidazothiazole moiety than theas
such parallel
60b, 61amethoxy
and 61bhybrids 58b,
showed
greater potency than the parallel methoxy hybrids 58b, 59a and 59b, which may due of
59a and 59b, which may due to the expected hydrogen bond with the hydroxyl group to
the receptor site.
the expected hydrogen bond with the hydroxyl group of the receptor site.
Bashandy reported on the preparation of benzenesulfonamide-based heterocycles
with expected anticancer activity [39]. Thus, acetophenone derivative 62 was treated with
bromine in a mixture of dioxane/diethyl ether to give the alpha bromoacetyl compound
63 (Scheme 15). Treatment of 62 with thiosemicarbazide yielded the thiosemicarbazone
moiety 64, which, when heated with phenacyl bromide compound 63, produced the
thiazole derivative 65.
The interaction of phenacyl bromide compound 63 with thiosemicarbazide furnished
the 2-hydrazinyl thiazole compound 67, instead of 2-aminothiadiazine derivative 66. Con-
densation of 67 with 4-fluorobenzyldehyde afforded the corresponding thiazolyl Schiff
base 68 which displayed good activity towards hepatocellular carcinoma [39] (Scheme 16).
Molecules
Molecules 26, x26,
2021,2021, FOR1449PEER REVIEW 11 of14
37of 42
Scheme 14. Synthesis

Scheme of derivatives
14. Synthesis 58a–c–61a–c.
of derivatives 58a–c–61a–c.
Bashandy reported on the preparation of benzenesulfonamide-based heterocycles

with expected anticancer activity [39]. Thus, acetophenone derivative 62 was treated with
bromine in a mixture of dioxane/diethyl ether to give the alpha bromoacetyl compound
63 (Scheme 15). Treatment of 62 with thiosemicarbazide yielded the thiosemicarbazone
moiety 64, which, when heated with phenacyl bromide compound 63, produced the thi-
azole derivative 65.
Scheme 15. Synthesis of Synthesis

Scheme 15. derivatives 63–65.
The interaction of phenacyl bromide compound 63 with thiosemicarbazide fur-

nished the 2-hydrazinyl thiazole compound 67, instead of 2-aminothiadiazine derivative
66. Condensation of 67 with 4-fluorobenzyldehyde afforded the corresponding thiazolyl
Schiff base 68 which displayed good activity towards hepatocellular carcinoma [39]
Scheme 15. Synthesis of derivatives 63–65.
The interaction of phenacyl bromide compound 63 with thiosemicarbazide fur-

nished the 2-hydrazinyl thiazole compound 67, instead of 2-aminothiadiazine derivative
66. Condensation of 67 with 4-fluorobenzyldehyde afforded the corresponding thiazolyl
Molecules 2021, 26, 1449 12 of 37
Schiff base 68 which displayed good activity towards hepatocellular carcinoma [39]
(Scheme 16).
Scheme 16.Scheme
Synthesis
16. of derivatives
Synthesis 67 and 68.67 and 68.
of derivatives
Cyclocondensation of
Cyclocondensation of 63 with phenyl
63 with phenyl thiosemicarbazide
thiosemicarbazidegavegavethiadiazine derivative
thiadiazine derivative
69. When compound 63 was treated with 2-aminothiazole and 2-aminobenzothiazole in
69. When compound 63 was treated with 2-aminothiazole and 2-aminobenzothiazole in
hot ethyl alcohol, it gave the corresponding imidazo[2,1-b]thiazole derivatives 70 and 71,
hot ethyl alcohol, it gave the corresponding imidazo[2,1-b]thiazole derivatives 70 and 71,
respectively (Scheme 17) [39]. Derivatives 69 and 71 presented a potent cytotoxicity against
respectively (Scheme 17) [39]. Derivatives 69 and 71 presented a potent cytotoxicity
monkey
both thekidney
human(VERO) (CC50) compared
liver hepatocellular carcinoma to the
cellconcentration thatmammalian
line (HepG2) and causes 50%cells
death
of in
against both the human liver hepatocellular carcinoma cell line (HepG2) and mammalian
the human liver hepatocellular carcinoma cell line (HepG2) (IC50).
the African green monkey kidney cell line (VERO).
cells of the African green monkey kidney cell line (VERO).
Meanwhile, derivative 70 showed good results in relation to the selectivity index
(SI), which is the ratio of the concentration that causes 50% death in the African green
Scheme 17. Synthesis of Synthesis

Scheme 17. derivatives 69–71.
A potent inhibitor of Src family kinases (SFKs) with slow dissociation rates, amino-
thiazole derivative 75 of dasatinib, in which the methylene unit substitutes the amide
linker between the moiety of thiazole and the aromatic ring of dasatinib, was prepared.
The phenyl acetaldehyde was firstly converted to 2-amino5-benzylthiazole 73, which was
Molecules 2021, 26, 1449 13 of 37
Meanwhile, derivative 70 showed good results in relation to the selectivity index (SI),
which is the ratio of the concentration that causes 50% death in the African green monkey
Scheme
kidney17. Synthesis
(VERO) of derivatives
(CC50) compared69–71.
to the concentration that causes 50% death in the human
liver hepatocellular carcinoma cell line (HepG2) (IC50).
AApotent
potentinhibitor
inhibitor of Src family
of Src familykinases
kinases(SFKs)
(SFKs) with
with slow
slow dissociation
dissociation rates,
rates, amino-
aminoth-
thiazole derivative 75 of dasatinib, in which the methylene unit substitutes
iazole derivative 75 of dasatinib, in which the methylene unit substitutes the amide linkerthe amide
linker between
between the moiety
the moiety of thiazole
of thiazole and the and the aromatic
aromatic ring ofring of dasatinib,
dasatinib, was prepared.
was prepared. The
The phenyl
phenyl acetaldehyde
acetaldehyde waswas firstly
firstly converted
converted to to 2-amino5-benzylthiazole
2-amino5-benzylthiazole 73, 73, which
which waswas
combined
combinedwithwith74,
74,aatype
type of
of Buchwald reaction(Scheme
Buchwald reaction (Scheme18)
18)[40].
[40].
Scheme 18.Scheme
Molecules 2021, 26, x FOR PEER REVIEW Synthesis
18. of derivatives
Synthesis 73 and 75.73 and 75.
of derivatives 17 of 42
AAseries
series of
of 2-pyridylamino-thiazoles
2-pyridylamino-thiazolesandand
2-pyridylamino,5-pyridylthiazoles contains
2-pyridylamino,5-pyridylthiazoles con-
a novel category of ATP-competitive Chk1 inhibitors with outstanding inhibitory poten-
tains a novel category of ATP-competitive Chk1 inhibitors with outstanding inhibitory
potential (Scheme
tial (Scheme 19) [41–43].
19) [41–43]. Modifications
Modifications of theofcore
thewith
core various
with various
amidesamides accommo-
accommodate
date compound
compound 77 with
77 with picomolar
picomolar potency
potency andhigh
and very veryresidence
high residence
times. times.
Scheme 19. Modification

19. Modification 76 and 76
of derivatives 77.and 77.
Someof
Some ofacylated
acylated 4-aryl-N-arylcarbonyl-2-aminothiazole
4-aryl-N-arylcarbonyl-2-aminothiazole scaffolds were
7878
scaffolds designed
were designed
and synthesized as highly active Hec1/Nek2 inhibitors. The fluoride derivative of 78
(Scheme 20) pointed to selectivity toward cancer cells over normal phenotype cells and
was inactive in a [3H]astemizole rival binding assay for hERG liability screening. Thus,
2-aminothiazoles 78 (X = F, R = R1 = Me) are promising towards the discovery of a pre-
clinical candidate targeting Hec1/Nek2 [44].
Scheme 19. Modification of derivatives 76 and 77.
Molecules 2021, 26, 1449 14 of 37
Some of acylated 4-aryl-N-arylcarbonyl-2-aminothiazole scaffolds 78 were designed
was 33
wasinactive
inactiveininaa[ [H]astemizole
H]astemizole rival
rival binding
binding assay for hERG liability
liability screening.
screening. Thus,
Thus, 2-
aminothiazoles 78 (X 1 1Me) are promising towards the discovery of a preclinical
2-aminothiazoles 78 =
(XF,=RF,=RR= =
R = Me) are promising towards the discovery of a pre-
candidate targetingtargeting
clinical candidate Hec1/Nek2 [44]. [44].
Hec1/Nek2
Scheme 20. Synthesis of derivative

Scheme 20. Synthesis78.
of derivative 78.
Thevariety
The variety elements
elements were
were incorporated
incorporatedthrough
throughazomethine
azomethine linkage on on
linkage thethe C4 C4
hy-hy-
drazineterminus
drazine terminusin in2-arylaminothiazoles
2-arylaminothiazoles 82
82 using
using (CH
(CH33)2)CH-,
2 CH-,(CH
(CH3)23CHCH
)2 CHCH2-, 2
cyclohexyl
-, cyclohexyl
andCC
and 6H6H 5CH
5 CH 22-- fragments,
fragments, and
andenrichment
enrichmentofofthe
thechemical
chemicalspace
spacetheytheywere
werein in
was was as-
assessed
sessed (Scheme
(Scheme 21). Some 21).ofSome of the prepared
the prepared compounds
compounds were found
were found to be to be a type
a new new of type of
Aurora
Aurora
kinase kinase inhibitors
inhibitors [45]. [45].

Scheme of21.derivative
Synthesis 82.
of derivative 82.
Regarding the important role of Aurora family kinases which regulate events during
mitosis including centrosome maturation and chromosome segregation, the misregula-
tion of Aurora kinases due to genetic amplification and protein overexpression results in
Molecules 2021, 26, 1449 Scheme 21. Synthesis of derivative 82. 15 of 37
mitosis including centrosome maturation and chromosome segregation, the misregula-
tion of Aurora kinases due to genetic amplification and protein overexpression results in
mitosis including centrosome maturation and chromosome segregation, the misregulation
aneuploidy and may contribute to tumorigenesis. A series of
of Aurora kinases due to genetic amplification and protein overexpression results in aneu-
2-aminophenyl-5-halothiazoles 83 was synthesized from the reaction of 2,5 substituted
ploidy and may contribute to tumorigenesis. A series of 2-aminophenyl-5-halothiazoles
thiazoles with tert-butyl
83 was synthesized fromphenylcarbamate
the reaction of 2,5 (Scheme 22)thiazoles
substituted [46,47]. with
The synthesized deriva-
tert-butyl phenyl-
tives displayed
carbamate different
(Scheme activities
22) [46,47]. The on Aurora kinase
synthesized inhibition,
derivatives withdifferent
displayed decreased histone
activities
H3 serine 10 phosphorylation. To summarize SAR for aminothiazole Aurora
on Aurora kinase inhibition, with decreased histone H3 serine 10 phosphorylation. To inhibitors,
arrows indicate
summarize SAR the
forposition and nature
aminothiazole of each
Aurora substitution
inhibitors, arrows tested in the
indicate a biochemical
position and Au-
rora A kinase
nature of eachassay (Figure tested
substitution 1). in a biochemical Aurora A kinase assay (Figure 1).
Scheme
Scheme22.
22. Synthesis
Synthesis of derivative
derivative83.
83.
Figure1.1.SAR
Figure SARofof
aminothiazole
aminothiazole
83. 83.
A series of thiazole and thiazolopyridazines, both containing the 2-thioureido function,

A series of thiazole and thiazolopyridazines, both containing the 2-thioureido func
were evaluated for in vitro antitumor activity against a cancer cell line collection. 1-(4-chloro-
tion, were evaluated for in vitro antitumor activity against a cancer cell line
phenyl)-3-[4-oxo-7-(4-bromo-phenyl)-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl]thiourea collection
deriva-
1-(4-chloro-phenyl)-3-[4-oxo-7-(4-bromo-phenyl)-4,5-dihydrothiazolo[4,5-d]pyridazin-2-
tive 1
88 (R = Cl, Ar = 4-BrC6 H4 ) proved lethal to the HS 578T cancer breast cell line with an
yl]thiourea
IC50 value of 0.8derivative 88 (R
µM. The title 1 = Cl, Ar = 4-BrC6H4) proved lethal to the HS 578T cance
thiourea derivatives 85 were synthesized by reaction of ethyl
breast cell line with an IC84
2-aminothiazole-4-carboxylate 50 value of 0.8isothiocyanate
with phenyl µM. The title thioureaThen,
derivatives. derivatives 85 were syn
the functional
thesized
esters wereby reaction
reacted with NHof 2ethyl
NH2 to 2-aminothiazole-4-carboxylate
give the acid hydrazides 86, which84 with
were phenyl
treated isothiocya
with the
benzoyl chlorides to afford the corresponding 3-phenylthioureas An in situ
nate derivatives. Then, the functional esters were reacted with NH2NH2 to give the acid
87. cyclization was
carried out on compound 87 to afford the thiazolo[4,5-d]pyridazin-2-yl]thiourea derivatives
hydrazides 86, which were treated with the benzoyl chlorides to afford the correspond
88 (Scheme 23) [48]. The derivative 88 which contains (R1 = Cl; Ar = 4-BrC6 H4 ) proved to be
ing 3-phenylthioureas 87. An in situ cyclization was carried out on compound 87 to af
the most active DHFR inhibitor with an IC50 of 0.06 µM and showed 31.4, 25.2, 37.7, 25.1 and
fordGI%
41.0 theagainst
thiazolo[4,5-d]pyridazin-2-yl]thiourea
NCI-H522 non-small cell lung, HT29 colon, derivatives
SK-OV-3 88ovarian,
(Scheme MCF723) breast
[48]. The de
rivative 88 which contains (R 1= Cl; Ar = 4-BrC6H4) proved to be the most active DHFR
and T-47D breast cancers, respectively. Meanwhile, derivatives of compound 88 that contain
inhibitor
(R 1 = Cl, OCHwith an IC
3 ; Ar= OCH50 of 0.06 3µM
3 , OCH and
) were showed
active 31.4,
with an IC5025.2,
of 0.137.7, 25.1µM,
and 2.5 and 41.0 GI% agains
respectively.
NCI-H522
In non-smallof cell
addition, derivatives lung, HT29
compound colon, (R
88 that contain SK-OV-3 3ovarian, MCF7 breast and T-47D
1 = OCH ; Ar = Ph) showed antitumor
breast cancers, respectively. Meanwhile, derivatives of compound 88 that contain (R1

Cl, OCH3; Ar= OCH3, OCH3) were active with an IC50 of 0.1 and 2.5 µM, respectively. In
addition, derivatives of compound 88 that contain (R1 = OCH3; Ar = Ph) showed anti
tumor activity against NCI-H522 non-small cell lung, HT29 colon and TK-10 renal with
Molecules 2021, 26, 1449 16 of 37
Molecules 2021, 26,

Molecules 2021, 26, xx FOR
FOR PEER
PEER REVIEW
REVIEW 20 of 42
activity against NCI-H522 non-small cell lung, HT29 colon and TK-10 renal with GI values20ofof 42
31.7, 29.4 and 34.7%, respectively.
Scheme
Scheme 23.
23. Synthesis
Synthesis
Schemeof
of23.derivative
derivative 88.
Synthesis 88.
of derivative 88.
2. 2-Aminothiazoles
2.2.2.
2-Aminothiazoles
2-Aminothiazoles
as Antioxidant
as as
Antioxidant Agents.
AntioxidantAgents.
Agents
The
The energy
The energy production
productiontoto
energy production to fuel
fuel
fuel biological
biological
biological processes
processes
processes by
by oxidation
by oxidationoxidation is
is important
is important to many to
important to
many
many living
living living organisms.
organisms.
organisms. The outcomes
The outcomes
The outcomes indicated
indicated indicated that, the synthesized
that, the derivative
that, the synthesized synthesized derivative
derivative
4-amino-5-
4-amino-5-benzoyl-2-(4-methoxyphenyl-amino)thiazole
4-amino-5-benzoyl-2-(4-methoxyphenyl-amino)thiazole
benzoyl-2-(4-methoxyphenyl-amino)thiazole (89) (Scheme (89)
24)(Scheme
(89) (Scheme
pointed to24)
24)anpointed
pointed
importantto
to an
an
important
antioxidant antioxidant
potential inpotential
terms of in terms
scavenging of
freescavenging
radicals. In free radicals.
addition,
important antioxidant potential in terms of scavenging free radicals. In addition, In addition,
4-aminothiazole
4-aminothiazole
hybrid 89 was anhybrid
4-aminothiazole effective89
hybrid was
89radio an
an effective
wasprotector against
effective radio protector
protector against
radiation-induced
radio damage
against radiation-induced
in the liver of
radiation-induced
damage
damage in the liver of mice. In addition, 4-aminothiazole scaffold 89 can protect
mice. Inin the liver
addition, of mice.
4-aminothiazoleIn addition,
scaffold 894-aminothiazole
can protect the scaffold
mouse 89 can
myocardium againstthe
protect the
mouse
damage myocardium
and one of against
the damage
possible reasons and one
behind of
thisthe possible
protective reasons
effect
mouse myocardium against damage and one of the possible reasons behind this protec-
can behind
be this
attributed protec-
to its
tive
tive effect
effect can
antioxidant
can be
be attributed
attributed to
property [49–51]. its antioxidant property [49–51].
to its antioxidant property [49–51].
Scheme
Scheme 24.
24. Synthesis
Schemeof
Synthesis 24.derivative
of Synthesis 89.
derivative of derivative 89.
89.
The 4-(thiazol-2-yl-azo)-2,4-dihydro-3H-pyrazol-3-one scaffold
The was blended by by
a
The 4-(thiazol-2-yl-azo)-2,4-dihydro-3H-pyrazol-3-one scaffold 9191
4-(thiazol-2-yl-azo)-2,4-dihydro-3H-pyrazol-3-one
diazo-coupling reaction of 3-methyl-1-phenyl-5-pyrazolone scaffold
with 91 was
was blended
2-aminothiazoleblended
(8) andby aa
diazo-coupling
diazo-coupling reaction of of 3-methyl-1-phenyl-5-pyrazolone with 2-aminothiazole (8)
(8) and
ferric hydrogenreaction 3-methyl-1-phenyl-5-pyrazolone
sulfate (Scheme 25). The synthesized thiazole with 2-aminothiazole
scaffolds 90 and 91 were and
ferric
ferric hydrogen
hydrogen sulfate
sulfate (Scheme
(Scheme 25).
25). The
The synthesized
synthesized thiazole
thiazole scaffolds
scaffolds 90
90 and
and 91
91 were
were
assessed for an antioxidant effect, and among them, Cu(II) Co(II) and Ni(II) complexes
assessed
assessed for an
an antioxidant effect, and among them, Cu(II) Co(II)
Co(II) and
and Ni(II)
Ni(II) complexes
indicatedfor
good antioxidant
activity in DPPHeffect,
andand among
nitric oxidethem, Cu(II)[52].
scavenging complexes
indicated good activity in DPPH and nitric oxide scavenging
indicated good activity in DPPH and nitric oxide scavenging [52]. [52].
Molecules 26, 1449
2021, 26,
Molecules 2021, x FOR PEER REVIEW 17 of
21 of 42
37

Scheme of25.derivative
Synthesis91.
of derivative 91.
Scheme 25. Synthesis of derivative 91.
A reactivity
A reactivity study
study ofof both
both the
the aryl
aryl substituent
substituent andand amino
amino group
group ofof aa novel
novel synthe-
synthe-
A reactivity study of both the aryl substituent and amino group of a novel synthe-
sized
sized 2-amino-5-(4-acetylphenylazo)-thiazole compound and its scaffolds via different elec-
sized2-amino-5-(4-acetylphenylazo)-thiazole
2-amino-5-(4-acetylphenylazo)-thiazole compound compoundand anditsitsscaffolds
scaffolds viavia different
different
trophilic reagents
electrophilic was conducted. They were biologically evaluated in vitro inand in vivo for
electrophilicreagents
reagents was
was conducted.
conducted. TheyTheywere
werebiologically
biologically evaluated
evaluated vitro
in vitro andandin in
their
vivo toxicity and antioxidant activity based on liver function enzymes. The new 2-amino-
vivofor
fortheir
theirtoxicity
toxicity and
and antioxidant activitybased
antioxidant activity basedon onliver
liverfunction
function enzymes.
enzymes. TheThenewnew
5-(4-acetylphenylazo)-thiazole (92) was(92)
2-amino-5-(4-acetylphenylazo)-thiazole reacted with
wasreacted
reactedvarious active
withvarious
variouscarbonyl
active reagents
carbonyl
2-amino-5-(4-acetylphenylazo)-thiazole (92) was with active carbonyl
(Scheme (Scheme
reagents 26) [53]. A convenient acetylation reaction ofreaction
92 by solvent-free acetylationacety-
with
reagents (Scheme 26) 26) [53].
[53]. A convenient
A convenient acetylation
acetylation reaction ofof 9292byby solvent-free
solvent-free acety-
acetic
lation anhydride
lationwith
withacetic
afforded
acetic anhydride
the N-acetylated
afforded the
anhydride afforded
product
theN-acetylated 93.
N-acetylatedproduct The electrophilic
product93.93. TheThe attack
electrophilic
electrophilic
of the
at- at-
benzoyl
tack cation
tackofofthe towards
thebenzoyl
benzoyl cation 92 yielded
cation towards
towards 92 the benzoyl
92 yielded
yieldedthe amino
thebenzoyl derivative
benzoylamino
amino 94. A
derivative
derivative further
94.94. reaction
A further
A further
of the highly
reaction of activated
the highly chloroacetyl
activated chloride
chloroacetyl reagent
chloride with
reagent 92 under
reaction of the highly activated chloroacetyl chloride reagent with 92 under basic
with 92 basic
under conditions
basic was
condi-
condi-
performed
tionswas
tions to produceto
wasperformed
performed tothe chloroacetyl
produce
produce the amino derivative
the chloroacetyl
chloroacetyl amino 95 [53]. 9595
aminoderivative
derivative [53].
[53].
(MeCO)22O Ac
Ac SS
(MeCO) O NN NHCOMe
NHCOMe
oo
60-70 C,
60-70 C, 22 hh NN
NN
9393(52%)
(52%)
Ac S Ac
Ac N S NH Ac S
NH22 PhCOCl N S NHCOPh
NN PhCOCl N N NHCOPh
N N pyridine, rt, 4 h N
N pyridine, rt, 4 h N
92 N
92 94 (53%)
94 (53%)
Ac S
ClCH2COCl Ac N NHCOCH2Cl
ClCH S
2COCl
DMF/Et N N NHCOCH2Cl
3N N
DMF/Et
rt, 4 h3N
N
N
95 (76%)
rt, 4 h
95 (76%)
Scheme 26.Scheme
Synthesis
26.ofSynthesis
derivatives
of 93–95.
Claisen–Schmidt condensation
Claisen–Schmidt condensation of of 2-acetylamino-5-(4-acetyl-phenylazo)-thiazole
2-acetylamino-5-(4-acetyl-phenylazo)-thiazole 93 93
withClaisen–Schmidt
with anequimolar
an equimolar ratio
ratio of aromatic
aromatic and/or
condensation
of and/or heterocyclic
heterocyclicaldehydes
aldehydesin in
sodium
sodiumhydroxide
of 2-acetylamino-5-(4-acetyl-phenylazo)-thiazole 93
hydroxide
and
and water/ethanol
water/ethanol medium
medium led
led to
to the
the formation
formation of
of chalcones
chalcones which
which reacted
reacted
with an equimolar ratio of aromatic and/or heterocyclic aldehydes in sodium hydroxide with
with hydra-
hydrazine
zinewater/ethanol
and hydrate
hydrate in the in the
presencepresence
medium led of
of ethanol ethanol
to afford
to the to96afford
formation (Scheme 96 (Scheme
27). The
of chalcones 27).reacted
The of
reaction
which reaction of
5-arylazo-2-
with hydra-
zine hydrate in the presence of ethanol to afford 96 (Scheme 27). The reaction of
Molecules
Molecules 2021, 26, 26,
2021, 1449x FOR PEER REVIEW 22 of
1842
of 37
5-arylazo-2-aminothiazole 92 with the appropriate aldehydes (two moles) under the

aminothiazole
same reaction 92 with theled
conditions appropriate aldehydes
to the formation of the(two moles) under
chalcone-imine the same97reaction
derivatives [53].
conditions led to the formation of the chalcone-imine derivatives 97
The synthesized derivatives 96 (R = 3-methylthiopnene) and 97 (R = indole) [53]. The showed
synthesized
a
derivatives
significant 96 (R = 3-methylthiopnene)
increase in antioxidant enzymeandactivities
97 (R = inindole) showed
the treated rat agroups
significant increase
at doses of
in50
antioxidant enzyme activities in the treated rat groups at doses of 50 and 100 mg/kg.
and 100 mg/kg.
Scheme Scheme
27. Synthesis of derivatives
27. Synthesis 96 and 97. 96 and 97.
of derivatives
Thetreatment
The treatment of phthalazin-1(2H)-one
of phthalazin-1(2H)-one andand 6-phenylpyridazin-3(2H)-one
6-phenylpyridazin-3(2H)-one com-
compounds
pounds with ethyl bromoacetate produced the ester derivatives 98. The
with ethyl bromoacetate produced the ester derivatives 98. The reactions of compounds reactions of 98
compounds 98 with hydrazine hydrate afforded the hydrazide derivatives
with hydrazine hydrate afforded the hydrazide derivatives 99a and 99b. Then, compounds 99a and 99b.
Then,
100 compounds
hydrazine 100 hydrazine
carbothioamide carbothioamide
moieties moietiesby
were prepared were
theprepared
reaction by the reaction 99
of compound
of compound
with potassium 99 with potassium
thiocyanate thiocyanate
in the presence in the presence
of hydrochloric acidof(Scheme
hydrochloric acid
28). Finally,
(Scheme 28). Finally,
hydrazinothiazoles 101hydrazinothiazoles 101 were blended
were blended by cyclization by cyclization
key intermediates key
100 withinterme-
suitable
diates 100
phenacyl with suitable
bromides phenacyl
in ethanol [54]. bromides
Althoughinthe ethanol [54]. Although
synthesized the 101a,b
derivatives synthesized
demon-
derivatives
Molecules 2021, 26, x FOR PEER strated
REVIEW 101a,b demonstrated good antioxidant activity, particularly in
good antioxidant activity, particularly in the DPPH radical scavenging assay, theirthe
23 of DPPH
42
radical scavenging
inhibition activity onassay, their inhibition
cholinesterase activity
enzymes on cholinesterase
suggested enzymes suggested
a structure-specific interaction. a
structure-specific interaction.
SchemeScheme
28. Synthesis of derivatives
28. Synthesis 99–101.
3. 2-Aminothiazoles as Antimicrobial Agents.

Thiazole and imidazole scaffolds are an essential kind of heterocyclic compound.
They occupy a significant position in medicinal chemistry, showing a wide range of bio-
Molecules 2021, 26, 1449 19 of 37
2.3. 2-Aminothiazoles as Antimicrobial Agents

Thiazole and imidazole scaffolds are an essential kind of heterocyclic compound. They
occupy a significant position in medicinal chemistry, showing a wide range of bioactivi-
ties. A series of 4-(2-N-butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl-methyl-biphenyl-
2 carboxylic acid-(substitutedphenyl-thiazole)-amides 106 was prepared as outlined in
Scheme 29 by the conversion of the carboxylic acid derivative 105 into its acid chloride fol-
lowed by acylation with many 2-aminothiazoles. The newly synthesized title compounds
were screened for their in vitro antibacterial activity against S. Aureus and B. Subtilis and
Molecules 2021, 26, x FOR PEER REVIEW 24 ofof42the
also for an in vitro antifungal effect against C. Albicans and Aspergillus niger. Some
compounds exhibited encouraging outcomes [55].
Scheme
Scheme29.
29.Synthesis
Synthesisof
Scheme 29.ofderivative
Synthesis 106.
derivative 106.
of derivative 106.
The
Thecondensation
The condensationof
condensation of 3,4,5-trimethoxybenzaldehyde
of 3,4,5-trimethoxybenzaldehyde
3,4,5-trimethoxybenzaldehyde 107 107with
107 with2-aminothiazole
with 2-aminothiazole
2-aminothiazole and/or
and/or
and/or
2-amino-4-(p-substituted/unsubstituted)-phenyl
2-amino-4-(p-substituted/unsubstituted)-phenyl thiazole
2-amino-4-(p-substituted/unsubstituted)-phenyl thiazole
thiazole 108
108 (Scheme
(Scheme
108 30)
30)
(Scheme was
was
30) reported
reported
was to to
reported
furnish
tofurnish
furnish the
the corresponding
thecorresponding
corresponding Schiff
Schiff
Schiffbases
bases
bases 109.
109.109.The
The effect
effect
The ofofof
effect three
three
three methoxy
methoxy
methoxy groups
groups
groupsin in the
thethe
in
carbon phenyl
carbonphenyl nucleus
phenylnucleus
nucleusonon the
onthe courseofof
thecourse of reactions
reactions
reactions with
with
with the
the
the substituted
substituted
substituted thiazole
thiazole
thiazole nucleus
nucleus
nucleus and
and
and
the the
thecompounds
compounds
compounds containing
containing
containing a nitro
a nitro nitro
group group
group
and and andfluoro
fluorofluoro atatpara
at para parapositions
positions
positions exhibited
exhibited
exhibited very very
very
good
goodactivity
good
activity activity against
againstagainst
both the both
both the i.e.,
the
strains, strains,
strains, i.e.,
i.e., the
the electron-withdrawing
electron-withdrawing
the electron-withdrawing group
group showedgroup showed
showed
maximum
maximum
maximum
inhibition in inhibition
inhibition in both
in bothonthe
both the strains strains
thestrains on
on the
antibacterial antibacterial
theand
antibacterial
antifungal and
and antifungal
antifungal
activities activities
of the of of
activities
synthesized
thesynthesized
the synthesized
products products [56].
[56]. products [56].

Scheme 30. Synthesis of derivative
Scheme 30. Synthesis 109.
of derivative 109.
Some derivatives of 2-aminothiazole bearing arylazo moiety at the fifth position
Some been
have derivatives
usedof 2-aminothiazole
for bearing arylazo
antimicrobial activities.moiety
Theat theamide
fifth position
of
have been used for antimicrobial
2-amino-4-phenyl-5-phenylazothiazoles activities.
derivatives 110 (Scheme 31) wasThe obtained
amidewhen of
2-amino-4-phenyl-5-phenylazothiazoles derivatives
2-amino-4-phenyl-5-phenylazothiazole was acylated 110 (Scheme
with 31) was
appropriate obtainedaro-
substituted when
2-amino-4-phenyl-5-phenylazothiazole
matic acid chlorides by employing thewas acylated with synthesis
Schotten–Bauman appropriate substituted
protocol. aro-
All the
Molecules 2021, 26, 1449 20 of 37
Some derivatives of 2-aminothiazole bearing arylazo moiety at the fifth position have
been used for antimicrobial activities. The amide of 2-amino-4-phenyl-5-phenylazothiazoles
derivatives 110 (Scheme 31) was obtained when 2-amino-4-phenyl-5-phenylazothiazole
was acylated with appropriate substituted aromatic acid chlorides by employing the
Molecules 2021, 26, x FOR PEER REVIEW
Schotten–Bauman synthesis protocol. All the synthesized compounds showed good25 of 42
an-
timicrobial activity against E. coli, S. aureus, A. niger and A. oryzaeto [57].

Schemeof31.derivative 110.
Synthesis of derivative 110.
Coupling
Coupling ofofdiazonium
diazonium saltssalts
with with 2-aminothiazole
2-aminothiazole derivative
derivative 111 provided 111theprovided
phenylazo-the
Coupling of
phenylazo-thiazole diazonium salts with 2-aminothiazole derivative 111 provided
seriesthe
thiazole derivatives derivatives 112yield
112 in excellent in excellent
(Schemeyield (Scheme
32). The 32). The
synthesized synthesized
series of benzamide-
phenylazo-thiazole
oflinked
benzamide-linked derivatives
2-aminothiazole-based 112 in excellent
2-aminothiazole-based
compounds showed yield (Scheme
compounds
excellent showed32).excellent
antibacterial The synthesized
activity antifun-series
antibacterial
and
ofactivity
benzamide-linked
and [58].
gal activity 2-aminothiazole-based
antifungal activity [58]. compounds showed excellent antibacterial
activity and antifungal activity [58].

Scheme of
32.derivative
Synthesis 112.
of derivative 112.
SchemeEthanoisobenzofuran-1,3-dione
32. Synthesis of derivative 112. (113) was obtained by the addition of maleic anhy-
Ethanoisobenzofuran-1,3-dione (113) was obtained by the addition of maleic anhy-
dride to cyclohexadiene. The reaction of 2-aminothiazole derivatives 114 and 115 with the
dride to cyclohexadiene. The reaction of 2-aminothiazole derivatives 114 and 115 with
the Ethanoisobenzofuran-1,3-dione
derivative (113) 113was obtained by
a the addition ofofmaleicnewanhy-
anhydride derivative 113 gave a group of new 2-(4-arylthiazol-2-yl)-3a,4,7,7a-tetrahydro-
anhydride gave group
1H-4,7-
dride ethanoisoindole1,3(2H)-dione derivatives
to cyclohexadiene. The reaction of 2-aminothiazole
116 and (Scheme 33). According
derivatives 114 and deriva-
117 115 with
2-(4-arylthiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-
to MIC values, derivatives 117 (R1 = OCH3 ) and 117 ethanoisoindole1,3(2H)-dione
(R1 = CH3 ) presented remarkable
the
tives anhydride
116 toward
and 117E.(Scheme derivative
33). According 113
to MIC gave a group of new
efficacy coli. Derivative 117 (R1 =H, R2 = values, derivatives
Ph) showed 117efficacy
significant (R1 = OCH 3) and
toward
2-(4-arylthiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-
117 (R1 = CH3) presented remarkable efficacy toward ethanoisoindole1,3(2H)-dione
E. coli. Derivative 117 (R1 =H, deriva-
R2 =
tives 116 and 117 (Scheme 33). According to MIC values, derivatives 117 (R 1 = OCH3) and
Ph) showed significant efficacy toward P. Aeruginosa. Derivatives 117 (R = 4-Br), 116 (n =
1
117 (R1 =117

0) and CH(R3) 1presented remarkable
= 4-Cl) displayed low efficacy and 117E.(Rcoli.
activity, toward Derivative
1 = OCH 117(R
3) and 117 (R1 1==H,
CHR 3) =
2
Ph) showed
showed significant
remarkable efficacy
efficacy toward
toward P. Aeruginosa.
S. marcescens. Derivatives
In summary, 117 (R1 active
the utmost = 4-Br), 116 (n =
deriva-
0)tives
andare
117117
(R (R=1 =4-Cl)
1
4-Cl)displayed
(MIC: 0.039low activity,
g/mL) and C.
toward 117 (R = OCH
perfringes
1
and3)117
and(R1117
= H)(R(MIC:
1 = CH3)
Molecules 2021, 26, 1449 21 of 37
P. Aeruginosa. Derivatives 117 (R1 = 4-Br), 116 (n = 0) and 117 (R1 = 4-Cl) displayed low
activity, and 117 (R1 = OCH3 ) and 117 (R1 = CH3 ) showed remarkable efficacy toward
S. marcescens. In summary, the utmost active derivatives are 117 (R1 = 4-Cl) (MIC: 0.039
µg/mL) toward C. perfringes and 117 (R1 = H) (MIC: 0.078 µg/mL) toward A. tumefacens.
Regarding SAR, derivatives 117 containing 4-Br and 4-Cl groups were established to be the
utmost active compounds according to the inhibition zone. They displayed particularly
high efficacy toward the utmost utilized microorganisms [59].

33. Synthesis 116 and116
The target
The target naphthalimide
naphthalimide aminothiazoles
aminothiazoles 121a–d and 122a–e
121a–d and were
122a–esynthesized through
were synthesized
multi-step reactions beginning from 4-bromo-1,8-naphthalic anhydride 118 according to
through multi-step reactions beginning from 4-bromo-1,8-naphthalic anhydride 118 ac-
Scheme 34. Condensation of 118 and thiosemicarbazide gave compound 119, which was
cording to Scheme 34. Condensation of 118 and thiosemicarbazide gave compound 119,
further cyclized with the α-halogenated carbonyl compounds to afford aminothiazole
which was120.
scaffolds further cyclized
Compound 120with
was the α-halogenated
further carbonylamines
treated with alicyclic compounds to afford
to give 121a-d. Theami-
nothiazole scaffolds 120. Compound 120 was further treated with alicyclic
N-alkylation of piperazine with alkylhalides generated mono-substituted alkyl piperazines amines to give
121a-d. The N-alkylation of piperazine with alkylhalides generated mono-substituted
122a−e. Piperazinyl derivatives effectively prevent the growth of methicillin-resistant S.
alkyl
Aureuspiperazines 122a−e.
and E. coli with MICPiperazinyl
values of 4 derivatives
and 8 µg/mL, effectively prevent
respectively. the growth
The utmost active of
methicillin-resistant S. Aureus and E. coli with MIC values of 4 and 8 µg/mL,
derivative 121d with the NH free piperazine moiety (MIC. values from 2 to 128 micromolar) respectively.
The utmostthe
displayed active
mostderivative 121d with
toxicity toward the NH free
Gram-positive piperazine
bacteria such asmoiety (MIC.
S. aureus 29213 values from
and au-
reus225923
to 128andmicromolar) displayed
was also effective the most
in inhibiting toxicity toward
Gram-negative bacteriaGram-positive
such as E. coli, E. bacteria
coli
such S. aureusand
25922,asP. aeruginosa 29213 and aureus
P. aeruginosa 27853 25923
at lowand was also These
concentrations. effective in inhibiting
designated 121d
Gram-negative bacteria such as E. coli, E. coli 25922, P. aeruginosa and P. aeruginosa 27853
had massive potentiality to be more effective broad-spectrum antimicrobial agents. In addi-
attion,
lowthe extents of alkylThese
concentrations. chainsdesignated
possess diverse121deffects on biological
had massive efficacy as
potentiality to in
bederivative
more effec-
122b with the hexyl group, which provided enhanced antibacterial
tive broad-spectrum antimicrobial agents. In addition, the extents of alkyl chains efficacy in contrast to
possess
furthereffects
diverse alkyl derivatives.
on biological Likewise,
efficacywhenas in the alkyl substituents
derivative 122b withwere lengthy
the hexyl to decyl,
group, which
dodecyl and hexadecyl groups, derivatives 122c–e showed weak activity in preventing the
provided enhanced antibacterial efficacy in contrast to further alkyl derivatives. Like-
growth of the examined bacteria. This real idea presented that only an appropriate alkyl
wise, when the alkyl substituents were lengthy to decyl, dodecyl and hexadecyl groups,
length chain in the piperazine ring was essential for a respectable antibacterial efficacy [8].
derivatives 122c–e showed weak activity in preventing the growth of the examined bac-
teria. This real idea presented that only an appropriate alkyl length chain in the pipera-
zine ring was essential for a respectable antibacterial efficacy [8].
Molecules
Molecules 2021, 26,xx1449
2021,26,
Molecules2021, 26, FOR
FORPEER
PEERREVIEW
REVIEW 22of
27
27 of42
of 37
42
SS SS
RR
HN
HN NH
NH22 HN
HN NN
OO OO OO OO OO NN OO
OO NN OO
Cl
Cl
thiosemicarbzide
thiosemicarbzide RR
DMF,
DMF,100
100 C,
C,8h
8h EtOH,
EtOH,80
80 C,
C,77hh
Br
Br RR==H,
118 Br
Br H,Me,
Me,3-NO
3-NO22CC66HH44 Br
Br
118
119
119(60%)
(60%) 120
120(21-40%)
(21-40%)
()
NN ( )nnCH
CH33 MeOCH
MeOCH22CH
CH22OH
OH MeOCH
MeOCH22CH
CH22OH
OH HN
HN ZZ
HN
HN ,,N,
N,77hh ,,N,
N,77hh (())nn
HH33CC OO OO
ZZ NN
)n NN
(()n NN
(()n
)n NN NH
NH
NN NH
NH
SS SS
OO NN OO NN
121a-d
121a-d(30-46%)
(30-46%)
122a-e
122a-e(26-40%)
(26-40%)
121:
121:a,a,nn==0,
0,ZZ==CH
CH22;;
122:
122: a, n = 3; b,
a, n = 3; b,nn==5;
5;c,c,nn==9;
9; b,
b, n = 1, Z =CH22;;
n = 1, Z =CH
d,
d,nn==11;
11;e,e,nn==15
15 c,c,nn==1,
1,ZZ==O;
O;
d,
d, n = 1,ZZ==NH
n = 1, NH
Scheme
Scheme34. Synthesis
34.Scheme 34.of
Synthesis ofderivatives
derivatives
Synthesis 119–117.
119–117. 119–117.
of derivatives
AA group
A group
group of imidazole-thiazole
ofimidazole-thiazole derivatives
imidazole-thiazolederivatives 123a–l
derivatives123a–l
123a–l were
were blended
blended
were blended using
using thethe
using the green
green pro-
green
protocol
tocol (Scheme
(Scheme 35).
35). The
The synthesized
synthesized derivatives
derivatives 123a–l were assessed
assessed for
for
protocol (Scheme 35). The synthesized derivatives 123a–l were assessed for their in vitro
123a–l their
their in
invitro
vitro
antifungal
antifungalactivity,
antifungal activity, and
activity, andthe compounds
thecompounds
compounds123j123j and
123jand 123k
and123k
123k inhibited
inhibited ergosterol
ergosterol
inhibited ergosterol biosynthesis
biosynthesis
biosynthesis by
by
by inhibiting
inhibiting enzyme
inhibiting enzyme cytochrome
enzyme cytochrome P450
cytochrome P450 P450 lanosterol
lanosterol 14α-demethylase
lanosterol 14α-demethylase of
14α-demethylase of C. of C.C. albicans.
albicans. albicans. The
The obtained
The
results suggest
obtained
obtained resultsthat
results these compounds
suggest
suggest that these might
that these inhibit fungal
compounds
compounds might lanosterol
might inhibit 14α-demethylase
inhibit fungal
fungal lanosterol
lanosterol
related to the accepted
14α-demethylase
14α-demethylase relatedmechanism
related to
tothe of fluconazole
theaccepted
accepted mechanism
mechanism [60].
of
offluconazole
fluconazole[60].
[60].
Scheme
Scheme35.
35.Synthesis of
Scheme 35.
Synthesis ofderivative
Synthesis 123a–l.
derivativeof derivative 123a–l.
123a–l.
AA seriesofof thiazolyl-thiourea derivatives 124 was synthesized bybythe addition reaction

A series
series of thiazolyl-thiourea
thiazolyl-thiourea derivatives
derivatives 124
124 was
was synthesized
synthesized by thethe addition
addition reac-
reac-
of
tion 2-aminothiazole to isothiocyanate (Scheme 36). The obtained thioureas were examined
tion of 2-aminothiazole to isothiocyanate (Scheme 36). The obtained thioureas were ex-
of 2-aminothiazole to isothiocyanate (Scheme 36). The obtained thioureas were ex-
in vitro against
amined a number of microorganisms. Initial antibacterial investigations found
amined in in vitro
vitro against
against aa number
number of
of microorganisms.
microorganisms. Initial
Initial antibacterial
antibacterial investigations
investigations
that halogen
found derivative of thiourea 124 has (3,4-dichlorophenyl) and 124 has (3-chloro-4-
found that
that halogen
halogen derivative
derivative of
of thiourea
thiourea 124
124 has
has (3,4-dichlorophenyl)
(3,4-dichlorophenyl) and and 124
124 has
has

Molecules 2021, 26, 1449 23 of 37
(3-chloro-4-fluorophenyl), which reveals the supreme promising efficacy toward staphy-

lococcal species. Generally, MIC results of S. aureus and S. epidermidis were displayed at 16
(3-chloro-4-fluorophenyl), which revealspromising
the supreme promising efficacy toward staphy-
to 4fluorophenyl),
µg/mL. These which reveals
thiourea the supreme
analogues were investigatedefficacy
totoward
explain staphylococcal
their abilityspecies.
to prevent
lococcal Generally, MIC results of S. aureus and S. epidermidis
Generally, MIC results of S. aureus and S. epidermidis were displayed at 16 to 4 µg/mL. at 16
species. were displayed
the formation of biofilms of eight methicillin-resistant strains of S. epidermidis (MRSE) [6].
to These
4 µg/mL. These
thiourea thiourea
analogues analogues
were were
investigated to investigated to explain
explain their ability theirthe
to prevent ability to prevent
formation
theofformation
biofilms ofof biofilms
eight of eight methicillin-resistant
methicillin-resistant of S. epidermidis
strains(MRSE)
strains of S. epidermidis [6]. (MRSE) [6].

Scheme of
36.derivative 124.
Chloro-4-(substitutedphenyl)-1--2-azetidinone compounds 128 (Scheme 37) were
synthesized in four dissimilar steps. 2-Aminothiazole
Chloro-4-(substitutedphenyl)-1–2-azetidinone 8 on128
compounds reaction
(Schemewith Cl(CH
37) were 2)2Br at
syn-
Chloro-4-(substitutedphenyl)-1--2-azetidinone compounds 128 (Scheme 37) were
room temperature
thesized gave 2-[(2-chloroethyl)
in four dissimilar amino]thiazole
steps. 2-Aminothiazole 8 on reaction 125.
withCompound
Cl(CH2 )2 Br 125 on reac-
at room
synthesized
temperature
ingave
four2-[(2-chloroethyl)
dissimilar steps. 2-Aminothiazole
amino]thiazole
8 on reaction
Compound on
with Cl(CH
reaction with
2)2Br at
tion with hydrazine hydrate at room
125. temperature
125 produced
room temperature
hydrazine hydrategaveat room2-[(2-chloroethyl)
temperature126. amino]thiazole
produced 125. Compound 125 on reac-
N-(2-hydrazinylethyl)-2
tion with
-
hydrazine
thiazolamine
hydrate
N-(2-hydrazinylethyl)-2-thiazolamine
Compound
at chosen
room
126 on further reaction with sev-
temperature produced
126. Compound 126 on further reaction with several substituted aromatic aldehydes
eral chosen substituted aromatic aldehydes yielded substituted benzaldehyde,
N-(2-hydrazinylethyl)-2 -thiazolamine
yielded substituted benzaldehyde, 126. Compound 126 on further reaction
2-[2-(thiazolylamino)–ethyl]–hydrazone compoundswith sev-
2-[2-(thiazolylamino)–ethyl]–hydrazone compounds 127. Compounds 127 on treatment
eral chosen substituted aromatic aldehydes
127. Compounds 127 on treatment with ClCH 2 COCl yielded substituted
in the presence of Et 3 N benzaldehyde,
furnished
with ClCH2COCl 128. in
Thethe presence of Etantitubercular
3N furnished compounds 128. The antimicrobial
2-[2-(thiazolylamino)–ethyl]–hydrazone
compounds antimicrobial and compoundsactivity
127. Compounds
of the newly127 on treatment
synthesized
andcompounds
antitubercular activity
bearing a of the newly
2-azetidinone synthesized
moiety exposed compounds
that all the bearingcompounds
evaluated a 2-azetidinone
with ClCH2COCl in the presence of Et3N furnished compounds 128. The antimicrobial
moiety
showed exposed
moderatethat
to all
good theantibacterial,
evaluated antifungal
compounds andshowed moderate
antitubercular to good
activities againstantibacte-
the
and antitubercular activity of the newly synthesized compounds bearing a 2-azetidinone
rial,chosen
antifungal andstrains
microbial antitubercular
[61]. activities against the chosen microbial strains [61].
moiety exposed that all the evaluated compounds showed moderate to good antibacte-
rial, antifungal and antitubercular activities against the chosen microbial strains [61].

Schemeof37.derivative 128.
SchemeSome
37. Synthesis of derivativethiazole
pyrazolone-linked 128. derivatives 133 containing substituents at 1,3,5-
Some pyrazolone-linked thiazole derivatives 133 containing substituents at
positions were synthesized according to Scheme 38. The commencing chalcones 132 were
1,3,5-positions were synthesized according to Scheme by38.reacting
The commencing chalcones 132
Some
made pyrazolone-linked
by conventional thiazolecondensation
Claisen–Schmidt derivatives 133 containing substituents at
suitably substituted
were made by conventional Claisen–Schmidt condensation by reacting suitably substi-
1,3,5-positions were synthesized according to Scheme 38. The commencing chalcones 132
tuted benzaldehydes and cyclopropyl-methyl ketone. 2-Aminothiazoles 129 were gained
were made by conventional Claisen–Schmidt condensation by reacting suitably substi-
by cyclocondensation of suitably substituted acetophenones with thiourea in the pres-
tuted benzaldehydes and cyclopropyl-methyl ketone. 2-Aminothiazoles 129 were gained
ence of bromine. Chloroacetamides 130 was obtained by reacting 2-aminothiazoles 129
by cyclocondensation of suitably substituted acetophenones with thiourea in the pres-
Molecules 2021, 26, 1449 24 of 37

benzaldehydes and cyclopropyl-methyl ketone. 2-Aminothiazoles 129 were gained by
cyclocondensation of suitably substituted acetophenones with thiourea in the presence
of bromine. Chloroacetamides 130 was obtained by reacting 2-aminothiazoles 129 with
with chloroacetyl
chloroacetyl chloride
chloride in thein the presence
presence of pyridine.
of pyridine. When chloroacetamides
When chloroacetamides 130 were
130 were heated
heated with hydrazine
with hydrazine hydratehydrate in ethanol,
in ethanol, hydrazineshydrazines 131 were When
131 were obtained. obtained. When132
chalcones chal-
cones 132 were heated with hydrazines 131 in dioxane containing a few drops
were heated with hydrazines 131 in dioxane containing a few drops of acetic acid, pyra- of acetic
acid, pyrazoline
zoline derivatives
derivatives 133 were
133 were gained. Thegained. The target compounds
target compounds 133 indicated133 indicated
more more
significant
significant antimicrobial
antimicrobial activity than activity thanstandard
some known some known standard
drugs, and drugs, and
most compounds most out
pointed com-
a moderate degree of potent antimicrobial activity [62].
pounds pointed out a moderate degree of potent antimicrobial activity [62].

Scheme of
38.derivative 133.
Seven2-amino-4-arylthiazole
Seven 2-amino-4-arylthiazole scaffolds 134a–gwere
scaffolds 134a–g weresynthesized
synthesized under microwave
under microwave
irradiation. Compounds 134a–f were reacted with (CH CO)
irradiation. Compounds 134a–f were reacted with (CH3CO)2O, C6H5COCl and
3 2 O, C 6 H 5 COCl and 2-furoyl
2-furoyl
chloride, respectively, to furnish thiazoles 135a–f, 136a–f and 137a–f (Scheme
chloride, respectively, to furnish thiazoles 135a–f, 136a–f and 137a–f (Scheme 39). 39). The reac-
The
tion of 134g with (CH3 CO)2 O led to the diacetyl derivative 139. The bromine derivatives
reaction of 134g with (CH3CO)2O led to the diacetyl derivative 139. The bromine deriva-
139a–f, 140a–f, 141a–f and 142 were obtained by the reaction of 2-amino-4-arylthiazoles,
tives 139a–f, 140a–f, 141a–f and 142 were obtained by the reaction of
N-(4-arylthiazol-2-yl)-acetamides, N-(4-arylthiazol-2-yl)- benzamide, furan-2-carboxylic
2-amino-4-arylthiazoles, N-(4-arylthiazol-2-yl)-acetamides,
acid (4-aryl-thiazol-2-yl)-amide and acetic acid 4-(2-acetylamino-N-(4-arylthiazol-2-yl)-
thiazol-4-yl)-phenyl ester ben-
zamide, furan-2-carboxylic
with molecular bromine under acid acid (4-aryl-thiazol-2-yl)-amide
conditions [63]. The synthesized compounds and acetic
displayed acid
4-(2-acetylamino- thiazol-4-yl)-phenyl
a remarkable anti-giardial activity. ester with molecular bromine under acid condi-
tions [63]. The synthesized compounds displayed a remarkable anti-giardial activity.
Molecules 2021,
Molecules 26,26,
2021, 1449PEER REVIEW
x FOR 25 of
3037
of 42
Scheme 39. Scheme

Synthesis
39.ofSynthesis
derivatives 135–141. 135–141.
of derivatives
Refluxing of
Refluxing of compound
compound 2-amino-4-phenylthiazole
2-amino-4-phenylthiazolewith different
with aromatic
different aldehy-
aromatic alde-
des in ethanol produced the corresponding 2-arylideneamino-4-phenylthiazoles
hydes in ethanol produced the corresponding 2-arylideneamino-4-phenylthiazoles 143– 143–146
(Scheme 40) in good yields. Acylation of 2-aminothiazole 10 with various acyl halides
146 (Scheme 40) in good yields. Acylation of 2-aminothiazole 10 with various acyl halides
in dry pyridine produced the corresponding amides 147–149 (Scheme 40) in high yields.
in dry pyridine produced the corresponding amides 147–149 (Scheme 40) in high yields.
Amongst the synthesized compounds investigated for the antibacterial activity, compound
Amongst the synthesized
144 indicated compounds
the highest activity againstinvestigated for of
B. cereus. Some the
theantibacterial activity,out
compounds pointed com-
pound 144 indicated
low antimicrobial the highest
activities and someactivity against B. to
were incompetent cereus. Some inhibition.
demonstrate of the compounds
For the
pointed out low antimicrobial activities and some were incompetent
antifungal activity, all compounds pointed to outstanding outcomes against to demonstrate
C. Lunata [64].in-
hibition. For
A set of the antifungal
compounds wasactivity,
preparedall compounds
from pointed to outstanding
the 2-amino-4-(2-pyridyl) outcomes
thiazole derivative
against C. Lunata
150 which [64].
was been synthesized by α-bromination of 2-acetylpyridine followed by conden-
sation with thiourea. In the presence of mono-substituted carboxylic acids, 2-aminothiazole
150 underwent an EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide)-mediated cou-
pling to deliver the target amides 152. Compound 151 was gained via the reaction of
2-bromoacetylpyridine with phenylthiourea (Scheme 41). Compounds 153 and 154 were
obtained from the reaction of compound 150 with phenyl isocyanate and benzoyl isoth-
iocyanate, respectively [65]. The antimycobacterial efficacy results for the synthesized
Molecules 2021, 26, 1449 26 of 37
derivatives revealed that derivative 152 with a phenyl ring which had an amide linker at
position 2 had superior antimycobacterial efficacy that matched derivatives 151, 153 and
154 which had amino, urea and acylthiourea linkers, respectively. However, derivatives
152 with a thiazole, imidazole and 2-pyridyl ring, respectively, displayed no activities
toward Mycobacterium tuberculosis (M.tb). Meanwhile, analogues 152 with thiophene,
3-pyridyl, 4-pyridyl and the monosubstitution in the four position with 4-Br, 4-I, 4-CH3 SO2 ,
4-NH2 CO, 4-CN, 4-NO2 and 4-CF3 , respectively, enhanced the activity like the unsubsti-
tuted phenyl derivative. The position of the substitution on the phenyl had an influence on
Molecules 2021, 26, x FOR PEER REVIEW activity as demonstrated by the bromo-substituted compounds with activity of the para > 31 of 42
meta > ortho. Switching the 2-pyridyl substituent by a 3-pyridyl or 4-pyridyl resulted in
loss of antimycobacterial activity.
Scheme 40.
Scheme 40.Synthesis of 2-arylideneamino-4-phenylthiazoles
Synthesis of 2-arylideneamino-4-phenylthiazoles 143–146.
143–146.
Treatment of the available compound 2-aminothiazole-4-carboxylate 155 with 1-

A set of compounds
adamantanoyl chloride 156was prepared
in hot from the
tetrahydrofuran 2-amino-4-(2-pyridyl)
followed thiazole
by conversion to Weinreb amide deriva-
tive and
150Grignard
which was in thebeen synthesized
existence by α-bromination
of methyl magnesium of 2-acetylpyridine
bromide afforded 158 (Scheme 42)followed
[66]. by
condensation
Meanwhile, with thiourea.
the substituted In group
amino the presence of mono-substituted
in C-2 position carboxylic acids,
of the thiazole can accommodate
2-aminothiazole 150 substitutions,
a range of lipophilic underwent while an EDCI (1-ethyl-3-(3-dimethylaminopropyl)
the thiazole moiety is sensitive to modification. car-
The synthesized derivative 158 showed respectable activity against
bodiimide)-mediated coupling to deliver the target amides 152. Compound 151 was (M.tb) growth with sub-
micromolar minimum inhibitory concentrations being achieved. A demonstrative hybrid was
gained via the reaction of 2-bromoacetylpyridine with phenylthiourea (Scheme 41).
selective for mycobacterial species over other bacteria and was rapidly bactericidal against
Compounds
replicating153 and It154
(M.tb). waswere obtained
concluded that from the reaction
these derivatives of potential
have compound 150 with phenyl
for additional
isocyanate
progressand benzoyl
as novel isothiocyanate,
antitubercular agents. respectively [65]. The antimycobacterial efficacy
results for the synthesized derivatives revealed that derivative 152 with a phenyl ring
which had an amide linker at position 2 had superior antimycobacterial efficacy that
matched derivatives 151, 153 and 154 which had amino, urea and acylthiourea linkers,
respectively. However, derivatives 152 with a thiazole, imidazole and 2-pyridyl ring,
respectively, displayed no activities toward Mycobacterium tuberculosis (M.tb). Mean-
while, analogues 152 with thiophene, 3-pyridyl, 4-pyridyl and the monosubstitution in
Molecules 2021, 26, 1449 27 of 37
Treatment of the available compound 2-aminothiazole-4-carboxylate 155 with

1-adamantanoyl chloride 156 in hot tetrahydrofuran followed by conversion to Weinreb
amide and Grignard in the existence of methyl magnesium bromide afforded 158
(Scheme 42) [66]. Meanwhile, the substituted amino group in C-2 position of the thiazole
can accommodate a range of lipophilic substitutions, while the thiazole moiety is sensi-
tive to modification. The synthesized derivative 158 showed respectable activity against
(M.tb) growth with sub-micromolar minimum inhibitory concentrations being achieved.
A demonstrative hybrid was selective for mycobacterial species over other bacteria and
was rapidly bactericidal against replicating (M.tb). It was concluded that these deriva-
Scheme 41.Scheme
Synthesis
41. of derivatives
Synthesis 150–154. 150–154.
of derivatives
tives have potential for additional progress as novel antitubercular agents.
Treatment of the available compound 2-aminothiazole-4-carboxylate 155 with
1-adamantanoyl chloride 156 in hot tetrahydrofuran followed by conversion to Weinreb
amide and Grignard in the existence of methyl magnesium bromide afforded 158
(Scheme 42) [66]. Meanwhile, the substituted amino group in C-2 position of the thiazole
can accommodate a range of lipophilic substitutions, while the thiazole moiety is sensi-
tive to modification. The synthesized derivative 158 showed respectable activity against
(M.tb) growth with sub-micromolar minimum inhibitory concentrations being achieved.
A demonstrative hybrid was selective for mycobacterial species over other bacteria and
was rapidly bactericidal against replicating (M.tb). It was concluded that these deriva-
tives have potential for additional progress as novel antitubercular agents.
Synthesis of 2-aminothiazole derivatives 160a-f substituted with 4-hydroxy-chromene-

2-one at the position number 4 was reported from cyclization of 3-(2-bromoacetyl)-4-
hydroxy- chromene-2-one 159 with the corresponding thiourea derivatives (Scheme 43).
All synthesized compounds exhibited antibacterial and antifungal activity [67].
Synthesis of 2-aminothiazole derivatives 160a-f substituted with

4-hydroxy-chromene-2-one at the position number 4 was reported from cyclization of
3-(2-bromoacetyl)-4-hydroxy- chromene-2-one 159 with the corresponding thiourea de-
Molecules 2021, 26, 1449 28 of 37
rivatives (Scheme 43). All synthesized compounds exhibited antibacterial and antifungal
activity [67].

Scheme 43.of Synthesis
derivativeof160a–f.
derivative 160a–f.
Thesynthesis
The synthesis ofof new
new thiazole
thiazole derivatives 165and
derivatives 165 and166166from
fromdialkyl aminothiocar-
dialkyl aminothiocar-
bamides 163 and 164 with 2-bromo-(naphthalene-2-yl)ethanone) (Scheme 44) was consid-
bamides 163 and 164 with 2-bromo-(naphthalene-2-yl(ethanone) (Scheme 44) was con-
ered and their in vitro antimicrobial and anticancer activity was tested. The antimicrobial
sidered and their in vitro antimicrobial and anticancer activity was tested. The antimi-
properties of these naphthylthiazolylamine compounds were evaluated against various
crobial properties of these naphthylthiazolylamine compounds were evaluated against
selected bacterial and fungal strains using the minimum inhibitory concentration (MIC)
various
method. selected bacterial
In addition, and fungal
cytotoxicity strains
studies using
were alsothe minimum
carried inhibitory
out in Hep-G2 andconcentration
A549 cell
(MIC) method. In addition, cytotoxicity studies were also carried
lines to examine the ability of these compounds to inhibit cell growth [68]. out in Hep-G2 and
A549 cell
The lines to examine quinolones
2-aminothiazolyl the ability of
171these compounds
and 174 to inhibit
were synthesized cell growth
(Scheme 45) via[68].
multi-
step reactions. Ethyl (ethoxymethylene)-3-oxobutanoate was treated with 2,4-difluoroaniline
to furnish ethyl 2-((2,4-difluorophenylamino)methylene)-3-oxobutanoate (167), which was
then further recyclized in hot phenoxy-benzene to afford the needed 3-acetyl quinolone
168. Compound 168 was N-aralkylated or alkylated to afford N-aralkyl quinolones 169
and alkyl derivatives 172, which were then brominated to produce the corresponding 3-(2-
bromoacetyl)-quinolone derivatives 170 and 174. The cyclization of the bromoacetyl group
at the C-3 position of 170 and 173 with thiourea in ethyl alcohol at 60 ◦ C yielded aralkyl
2-aminothiazolyl quinolones 171 (R1 = H, F, Cl; R2 = H, F, Cl; R3 = H, F, Cl, NO2 ) and alkyl
derivatives 174 (R4 = n-propyl, n-pentyl, n-heptyl, n-decyl, n-dodecyl, CH2 C≡CH). The
new 2-aminothiazolyl quinolones’ in vitro antimicrobial activity could effectively restrain
the growth of some tested strains [69]. Antibacterial screening of the synthesized hybrids
exhibited that N-1 propargyl modified 2- aminothiazolyl quinolone 174, which presented
high antibacterial activities in contrast to the rest of the derivatives against B. typhi. Further,
this derivative exhibited equal or better activity in contrast to the two reference drugs
toward S. dysenteriae and P. aeruginosa. Likewise, it was found that a shorter carbon chain
such as the propyl derivative was more favorable in exerting antibacterial efficacy in com-
parison to norfloxacin and chloromycin as standard drugs. However, in the pentyl, octyl,
decyl and dodecyl chains, a decrease in antibacterial efficacy was observed. Meanwhile, the
monoflouroderivatives 171 were more active than the monochloro-derivatives 171. Mainly,
the derivative 171 with the substituent para chloro on the phenyl ring could prevent the
growth of S. dysenteriae (MIC = 4 mg/mL). Amazingly, the activities of derivative 171
with the electro-donating OCH3 group and 171 with the electro-withdrawing NO2 group
were not greatly diverse alongside the utmost strains and both presented comparably
weak bioactivity.
6, x FOR PEER REVIEW
Molecules 2021, 26, 1449 34 of 42 29 of 37

The 2-aminothiazolyl quinolones

The synthesis 171 and amide
of N-thiazolyl 174 were synthesizedderivatives
fluoroquinolone (Scheme 177a-d
45) viainvolved the
multi-step reactions. Ethyl
reaction (ethoxymethylene)-3-oxobutanoate
sequence was treated
of nucleophilic aromatic substitution followed with
by acid derivatization to
2,4-difluoroaniline amides (Scheme 46). to
Amino-substituted furnish
fluoroquinolone compounds ethyl
176a-d were gained
by heating 1,4-dihydroquinoline-3-carboxylic
2-((2,4-difluorophenylamino)methylene)-3-oxobutanoate acids
(167), 175 with
which wascyclic
thenamine in acetonitrile
further
and triethyl amine [70]. Further, the prepared derivatives were used to investigate non-
recyclized in hot phenoxy-benzene to afford the needed 3-acetyl quinolone 168. Com-
carboxylic acid fluoroquinolones with an objective to enhance the anti-staphylococcal
pound 168 was N-aralkylated or alkylated to afford N-aralkyl quinolones 169 and alkyl
activity and improve their toxicity profile.
derivatives 172, which were then brominated to produce the corresponding
3-(2-bromoacetyl)-quinolone derivatives 170 and 174. The cyclization of the bromoacetyl
group at the C-3 position of 170 and 173 with thiourea in ethyl alcohol at 60°C yielded
aralkyl 2-aminothiazolyl quinolones 171 (R1 = H, F, Cl; R2 = H, F, Cl; R3 = H, F, Cl, NO2)
and alkyl derivatives 174 (R4 = n-propyl, n-pentyl, n-heptyl, n-decyl, n-dodecyl, CH2
C≡CH). The new 2-aminothiazolyl quinolones’ in vitro antimicrobial activity could ef-
fectively restrain the growth of some tested strains [69]. Antibacterial screening of the
However, in the pentyl, octyl, decyl and dodecyl chains, a decrease in antibacterial effi-
cacy was observed. Meanwhile, the monoflouroderivatives 171 were more active than the
monochloro-derivatives 171. Mainly, the derivative 171 with the substituent para chloro
on the phenyl ring could prevent the growth of S. dysenteriae (MIC = 4 mg/mL). Amaz-
Molecules 2021, 26, 1449
ingly, the activities of derivative 171 with the electro-donating OCH3 group and 17130with
of 37
the electro-withdrawing NO2 group were not greatly diverse alongside the utmost strains
and both presented comparably weak bioactivity.

Scheme 45.Scheme
Synthesis
45. of derivatives
Synthesis 167–174. 167–174.
of derivatives
The synthesis of N-thiazolyl amide fluoroquinolone derivatives 177a-d involved the

reaction sequence of nucleophilic aromatic substitution followed by acid derivatization
to amides (Scheme 46). Amino-substituted fluoroquinolone compounds 176a-d were
gained by heating 1,4-dihydroquinoline-3-carboxylic acids 175 with cyclic amine in ace-
tonitrile and triethyl amine [70]. Further, the prepared derivatives were used to investi-
gate non-carboxylic acid fluoroquinolones with an objective to enhance the an-
ti-staphylococcal activity and improve their toxicity profile.
Scheme 46.Scheme
Synthesis
46.ofSynthesis
derivative
of177a–d.
derivative 177a–d.
From ř-bromoacetoacetanilides
From 149 and
ɷ-bromoacetoacetanilides 149 andthiourea/phenyl
thiourea/phenyl thioureas,
thioureas,a aseries of of
series 4-
arylacetamido-2-amino- and
4-arylacetamido-2-amino- and2-arylamino-1,3-thiazoles
2-arylamino-1,3-thiazoles waswas
180180 synthesized (Scheme
synthesized 47).
(Scheme
47). The compounds were assessed for their in vitro antibacterial, antifungal and anti-
oxidant activities [71].
Scheme 46. Synthesis of derivative 177a–d.
Molecules 2021, 26, 1449 31 of 37

From ɷ-bromoacetoacetanilides 149 and thiourea/phenyl thioureas, a series of
4-arylacetamido-2-amino- and 2-arylamino-1,3-thiazoles 180 was synthesized (Scheme
47). The compounds were assessed for their in vitro antibacterial, antifungal and anti-
oxidant activities were
The compounds [71]. assessed for their in vitro antibacterial, antifungal and antioxidant
activities [71].

Scheme of
47.derivative 180.
4.2.4.
2-Aminothiazoles
2-Aminothiazolesas as
Anti-Inflammatory
Anti-InflammatoryAgents.
Agents
The synthetic
The synthetic pathwaypathway used
used to synthesize to synthesize
the target the target thiazol-
thiazolyl-hydrazinomethylidene
yl-hydrazinomethylidene pyrazoles 184 and N-substituted anilinothiazoles
pyrazoles 184 and N-substituted anilinothiazoles 185 are described in (Scheme 48). The185 are de-
present
synthesis
scribed in of thiazolyl-hydrazinomethylidene
(Scheme 48). The present synthesis pyrazoles 184 makes up the condensationpyra-
of thiazolyl-hydrazinomethylidene of
appropriate
zoles 1846-substituted-3-bromoacetylcoumarin
makes up the 181 with suitable
condensation pyrazole-4-carbaldehyde
of appropriate
thiosemicarbazone 182 in the presence of181
6-substituted-3-bromoacetylcoumarin sodium
with acetate. 4-Thioureido-benzenesulfonamide
suitable pyrazole-4-carbaldehyde thio-
183 was treated with different 3-bromoacetylcoumarin compounds 182 in a hot mixture
semicarbazone 182 in the presence of sodium acetate. 4-Thioureido-benzenesulfonamide
of ethyl alcohol and tetrahydrofuran in the presence of CH3 COONa to give N-substituted
183 was treated with different 3-bromoacetylcoumarin compounds 182 in a hot mixture
anilinothiazole derivatives 185. All the synthesized thiazolyl-hydrazinomethylidene pyrazoles
of
Molecules 2021, 26, x FOR PEER REVIEW ethyl alcohol and tetrahydrofuran in the presence of CH 3 COONa to give N-substituted
37 of 42
184 and N-substituted anilinothiazoles 185 were assessed for there in vivo anti-inflammatory
anilinothiazole
activity [72]. derivatives 185. All the synthesized thiazolyl-hydrazinomethylidene py-
razoles 184 and N-substituted anilinothiazoles 185 were assessed for there in vivo an-
ti-inflammatory activity [72].

48. Synthesis 184 and 184
A series of thiazolyl derivatives 188, 190 and 191 was synthesized from the reactions
of 3-oxo-N-(thiazol-2-yl)butanamide 186 with hydroxylamine, salicylaldehyde and aro-
matic aldehyde derivatives through the next synthetic pathway as shown in Scheme 49.
Scheme 48. Synthesis of derivatives 184 and 185.
Molecules 2021, 26, 1449 32 of 37
A series of thiazolyl derivatives 188, 190 and 191 was synthesized from the reactions
of 3-oxo-N-(thiazol-2-yl)butanamide 186 with hydroxylamine, salicylaldehyde and aro-
A series ofderivatives
matic aldehyde thiazolyl derivatives
through188,the190
nextandsynthetic
191 was synthesized
pathway as from the reactions
shown of 49.
in Scheme
3-oxo-N-(thiazol-2-yl)butanamide 186 with hydroxylamine, salicylaldehyde
The synthesized derivatives displayed inhibitory activities toward both the COX-1 iso- and aromatic
aldehyde derivatives through the next synthetic pathway as shown in Scheme 49. The
zyme (IC50 = 1.00–6.34 µM range) and the COX-2 isozyme (IC50 = 0.09–0.71 µM range),
synthesized derivatives displayed inhibitory activities toward both the COX-1 isozyme
with
(ICCOX-2 selectivity indexes in the range of 3.03 to 16 in comparison with the COX-2
50 = 1.00–6.34 µM range) and the COX-2 isozyme (IC50 = 0.09–0.71 µM range), with
selective
COX-2 standard
selectivity drug celecoxib
indexes (COX-1,
in the range of 3.03IC = 7.21
to5016 µM, COX-2,
in comparison withICthe = 0.83 µM
50 COX-2 and S.I. =
selective
8.68) [73].
standard drug celecoxib (COX-1, IC50 = 7.21 µM, COX-2, IC50 = 0.83 µM and S.I. = 8.68) [73].
N
N O NOH OH
NH2OH.HCl Zn, AcOH
S N
EtOH/AcONa S ,1h
N Me N
,8h H
187 Me
188 (48%)
CHO
OH COCH
OH O N
N O O 3
N S Dimroth
S N Me Pyridine H rearrangment N O
H ,5h O Me
186 S N
189
190 (59%)
R
R NH2
N O HN
191a: R = H (74%)
Benezene/AcOH S 191b: R = OMe (60%)
N Me
125oC, 1 h H 191c: R = Cl (68%)
191
Recently, a new series of 2-aminothiazoles bonded with 2-methylthiobenzimidazole

was prepared to investigate their anti-inflammatory properties on cyclooxygenase (COX)
and lipoxygenase (15-LOX) enzymes’ inhibition Scheme 50. The synthesized hybrids
containing the acetyl group 195, phenyl thiosemicarbazone 196 and 1,3-thiazolines 197a-c
were demonstrated to be the most selective COX-2 as well as 15-LOX inhibitors, that is,
due to the fact they provided a collaboration of not only molecular volume advantages but
also steric, electronic, hydrogen bonding and hydrophobic advantages that are essential to
confirm the optimal molecular interactions with the specific biological boards and to inhibit
their biological responses. Currently, the importance of these derivatives connected to
diverse aromatic and heterocyclic rings for evolving innovative anti-inflammatory agents
with dual COX-2 /15-LOX enzyme inhibitory efficacy is avowed [74].
Finally, some new 4-(4-chlorophenyl)thiazol-2-amines 200 were prepared via cyclic
condensation of an α-bromoketone 199 and N-substituted thiourea 198 in anhydrous
ethanol, stirring under microwave irradiation at 80 ◦ C for 30 min. The synthesized hybrids
were examined to evaluate their inhibitory effectiveness against bovine pancreatic DNase I
(Scheme 51). The in vitro evaluation of DNase I inhibition was based on spectrophotometric
measurement of acid-soluble nucleotide formation at 260 nm. Inhibition of 5-LO activity
was determined both in an intact cell system using freshly isolated polymorphonuclear
leukocytes (PMNL) and in a cell-free assay using partially purified recombinant 5-LO, and
5- LO product formation was determined by HPLC. The synthesized hybrids reserved
DNase I with IC50 values under 100 µM, and the derivative with (R1 = H, R2 = phenol and
and lipoxygenase (15-LOX) enzymes’ inhibition Scheme 50. The synthesized hybrids
containing the acetyl group 195, phenyl thiosemicarbazone 196 and 1,3-thiazolines 197a-c
were demonstrated to be the most selective COX-2 as well as 15-LOX inhibitors, that is,
due to the fact they provided a collaboration of not only molecular volume advantages
Molecules 2021, 26, 1449 but also steric, electronic, hydrogen bonding and hydrophobic advantages that33 are of 37 es-
sential to confirm the optimal molecular interactions with the specific biological boards
and to inhibit their biological responses. Currently, the importance of these derivatives
connected
R3 = amidetogroup)
diverse aromatic
displayed and IC
a potent heterocyclic rings for evolving innovative an-
50 = 79.79 µM, where the crystal violet, used as
ti-inflammatory agents with dual COX-2 /15-LOX enzyme inhibitory
a positive control in the absence of a “golden standard”, exhibited efficacy
almost 5-fold is avowed
weaker
[74].
DNase I inhibition [75].
(R1 = H, R2 = phenol and R3 = amide group) displayed a potent IC50 = 79.79 µM, where the
crystal violet, used as a positive control in the absence of a “golden standard”, exhibited
almost 5-fold
Scheme weaker
50. Synthesis
Scheme of DNase
50. I of
derivative
Synthesis inhibition
derivative[75].
197a–c. 197a–c.
Finally, some new 4-(4-chlorophenyl)thiazol-2-amines 200 were prepared via cyclic

condensation of an α-bromoketone 199 and N-substituted thiourea 198 in anhydrous
ethanol, stirring under microwave irradiation at 80 °C for 30 min. The synthesized hy-
brids were examined to evaluate their inhibitory effectiveness against bovine pancreatic
DNase I (Scheme 51). The in vitro evaluation of DNase I inhibition was based on spec-
trophotometric measurement of acid-soluble nucleotide formation at 260 nm. Inhibition
of 5-LO activity was determined both in an intact cell system using freshly isolated
polymorphonuclear leukocytes (PMNL) and in a cell-free assay using partially purified
recombinant 5-LO, and 5- LO product formation was determined by HPLC. The synthe-
sized hybrids reserved DNase I with IC50 values under 100 µM, and the derivative with

Scheme of
51.derivative 200.
3. Conclusions.
3. Conclusions
The
The heterocycles
heterocycles ofof 2-aminothiazole
2-aminothiazole scaffolds
scaffolds occupy occupy a dominant
a dominant part in organ-
part in organic/medicinal
ic/medicinal
chemistry in relation to their reactivity and biological activity and mostly actand
chemistry in relation to their reactivity and biological activity mostly act
as pharma-
as pharmacophores. The present review summarizes the literature reports of the various
synthetic routes for 2-aminothiazole-containing molecules with four different biological
activities (namely, anticancer, antioxidant, antimicrobial and anti-inflammatory activi-
ties). The presented information in this review is valuable for future innovation. The
simple synthesis of 2-aminothiazole hybrids bids the structure–activity revisions of sev-
Molecules 2021, 26, 1449 34 of 37
cophores. The present review summarizes the literature reports of the various synthetic routes
for 2-aminothiazole-containing molecules with four different biological activities (namely, anti-
cancer, antioxidant, antimicrobial and anti-inflammatory activities). The presented information
in this review is valuable for future innovation. The simple synthesis of 2-aminothiazole hybrids
bids the structure–activity revisions of several substitutions of this multilateral pharmacophore.
Further, several 2-aminothiazoles and their derivatives were generally utilized as drugs in the
treatment of various diseases, which has led to their extensive improvements. Attributable to
their broad scale of biological activities, their skeleton variants have attracted the attention of
many biologists. This review highlighted the recently synthesized 2-aminothiazole-containing
compounds within the last thirteen years ago. Further, the synthetic strategies developed for the
admission of the recent 2-aminothiazole derivatives (N-substituted, 3-substituted, 4-substituted,
multi-substituted, aryl/alkyl substituents or acyl/other substituents) were presented. The
reported literature revealed several synthetic pathways of those 2-aminothiazoles related to
four different biological activities (anticancer, antioxidant, antimicrobial and anti-inflammatory
activities). It is hoped that this review will be useful in displaying the rationalistic designs of
2-aminothiazole-based medical synthetic pathways.
Author Contributions: All authors have equal contributions in software collections, writing—
original draft preparation, writing—review and editing. All authors have read and agreed to
the published version of the manuscript.
Funding: This research was funded by Deputyship for Research and Innovation, “Ministry of
Education” in Saudi Arabia through Project no. (IFKSURP-23).
Acknowledgments: The authors extend their appreciation to the Deputyship for Research & Inno-
vation, “Ministry of Education” in Saudi Arabia for funding this research work through the project
number IFKSURP-23.
Conflicts of Interest: The authors declare no conflict of interest.
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An Overview On Synthetic 2-Aminothiazole-Based Compounds Associated With Four Biological Activities

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4.6 6.

Abstract: Amongst sulfur- and nitrogen-containing heterocyclic compounds, the 2-aminothiazole

Academic Editors: Ari Koskinen and

Molecules 2021, 26, 1449. https://doi.org/10.3390/molecules26051449 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, x FOR PEER REVIEW 3 of 42

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Scheme 4.Scheme 4. Synthesis

Treatment of 3-ethoxyacryloyl chloride with either 2-methylaniline or 2-chloro-6-

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The synthesis of N-(5-(4-fluorophenyl)thiazol-2-yl)-3-(furan-2-yl)propanamide (31)

Scheme 6. Synthesis of 2-aminothiazole-5-carbamides 28.

Benzimidazole-thiazole derivatives were prepared by heating a mixture of equimo-

Benzimidazole-thiazole derivatives were prepared by heating a mixture of equimolar

Scheme 10. Scheme

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Compound 41 containing an aminothiazole moiety was heated with malononitrile in

Heterocyclization of 2-aminothiazole 8 with α-bromo-3-methoxyacetophenone

Molecules 2021, 26, x FOR PEER REVIEW 13 of 42

Scheme 13. Scheme

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Scheme 14. Synthesis

Bashandy reported on the preparation of benzenesulfonamide-based heterocycles

Scheme 15. Synthesis of Synthesis

The interaction of phenacyl bromide compound 63 with thiosemicarbazide fur-

The interaction of phenacyl bromide compound 63 with thiosemicarbazide fur-

Scheme 17. Synthesis of Synthesis

Scheme 19. Modification

Scheme 20. Synthesis of derivative

Scheme 21. Synthesis

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A series of thiazole and thiazolopyridazines, both containing the 2-thioureido function,

breast cancers, respectively. Meanwhile, derivatives of compound 88 that contain (R1

Molecules 2021, 26,

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Scheme 25. Synthesis

5-arylazo-2-aminothiazole 92 with the appropriate aldehydes (two moles) under the

3. 2-Aminothiazoles as Antimicrobial Agents.

2.3. 2-Aminothiazoles as Antimicrobial Agents

Scheme 30. Synthesis of derivative 109.

Scheme 31. Synthesis of derivative 110.

Scheme 32. Synthesis

117 (R1 =117

Scheme 33. Synthesis

AA seriesofof thiazolyl-thiourea derivatives 124 was synthesized bybythe addition reaction

Molecules 2021, 26, x FOR PEER REVIEW 28 of 42

(3-chloro-4-fluorophenyl), which reveals the supreme promising efficacy toward staphy-

Scheme 36. Synthesis of derivative 124.

Scheme 36. Synthesis

Scheme 37. Synthesis

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Scheme 38. Synthesis

Scheme 39. Scheme

Treatment of the available compound 2-aminothiazole-4-carboxylate 155 with 1-

Scheme 41. Synthesis of derivatives 150–154.

Treatment of the available compound 2-aminothiazole-4-carboxylate 155 with

Scheme 42. Synthesis of derivative 158.

Synthesis of 2-aminothiazole derivatives 160a-f substituted with 4-hydroxy-chromene-

Synthesis of 2-aminothiazole derivatives 160a-f substituted with

Scheme 43. Synthesis