A variety of 5-(2H-tetrazol-5-yl)-4-thioxo-2-(substituted phenyl)-4,5-dihydro-1,3-oxazin-6-ones (... more A variety of 5-(2H-tetrazol-5-yl)-4-thioxo-2-(substituted phenyl)-4,5-dihydro-1,3-oxazin-6-ones (3a-k) have been synthesized from 1,3-oxazine-5-carbonitriles (2a-k). The protocol represents an efficient, facile and novel route from easily available precursors to unprecedented structures that share 1,3-oxazine and tetrazole motifs of utmost value. All the synthesized compounds (3a-k) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3-oxazine-tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2-bromophenyl moiety was the most potent among the series with IC value 0.0371 ± 0.0018 μM as compared to the reference kojic acid (IC = 16.832 ± 0.73 μM). Inhibitory kinetics showed that compound 3d behaves as a competitive inhibitor. The molecular docking analysis was performed against target protein to investigate the binding mode. Moreover, compounds 3j and 3k displayed superior DPPH ra...
The tropylium ion is a non-benzenoid aromatic species that works as a catalyst. This chemical ent... more The tropylium ion is a non-benzenoid aromatic species that works as a catalyst. This chemical entity brings about a large number of organic transformations, such as hydroboration reactions, ring contraction, the trapping of enolates, oxidative functionalization, metathesis, insertion, acetalization, and trans-acetalization reactions. The tropylium ion also functions as a coupling reagent in synthetic reactions. This cation’s versatility can be seen in its role in the synthesis of macrocyclic compounds and cage structures. Bearing a charge, the tropylium ion is more prone to nucleophilic/electrophilic reactions than neutral benzenoid equivalents. This ability enables it to assist in a variety of chemical reactions. The primary purpose of using tropylium ions in organic reactions is to replace transition metals in catalysis chemistry. It outperforms transition-metal catalysts in terms of its yield, moderate conditions, non-toxic byproducts, functional group tolerance, selectivity, and...
A series of hydrazine-1-carbothioamides derivatives (3a–3j) were synthesized and analyzed for inh... more A series of hydrazine-1-carbothioamides derivatives (3a–3j) were synthesized and analyzed for inhibitory potential towards bovine carbonic anhydrase II (b-CA II) and 15-lipoxygenase (15-LOX). Interestingly, four derivatives, 3b, 3d, 3g, and 3j, were found to be selective inhibitors of CA II, while other derivatives exhibited CA II and 15-LOX inhibition. In silico studies of the most potent inhibitors of both b-CA II and 15-LOX were carried out to find the possible binding mode of compounds in their active site. Furthermore, MD simulation results confirmed that these ligands are stably bound to the two targets, while the binding energy further confirmed the inhibitory effects of the 3h compound. As these compounds may have a role in particular diseases, the reported compounds are of great relevance for future applications in the field of medicinal chemistry.
The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-me... more The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1H-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N–H ⋯ S and C–H ⋯ O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R22 (8) and R22 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⋯ H (59.5%), H ⋯ S/S ⋯ H (16.1%), and H ⋯ C/C ⋯ H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density fun...
The current study focused on the laboratory approach in conjunction with computational methods fo... more The current study focused on the laboratory approach in conjunction with computational methods for the synthesis and bioactivity assessment of unique 2-tetradecanoylimino-3-aryl-4-methyl-1,3-thiazolines (2a–2k). Processes included cyclizing 1-aroyl-3-arylthioureas with propan-2-one in the presence of trimethylamine and bromine. By using spectroscopic techniques and elemental analyses, structures were elucidated. To assess the electronic properties, density functional theory (DFT) calculations were made, while binding interactions of synthesized derivatives were studied by the molecular docking tool. Promising results were found during the evaluation of bioactivity of synthesized compounds against alkaline phosphatase. The drug likeliness score, an indicator used for any chemical entity posing as a drug, was within acceptable limits. The data suggested that most of the derivatives were potent inhibitors of alkaline phosphatase, which in turn may act as lead molecules to synthesize de...
Urease is an amidohydrolase enzyme that is responsible for fatal morbidities in the human body, s... more Urease is an amidohydrolase enzyme that is responsible for fatal morbidities in the human body, such as catheter encrustation, encephalopathy, peptic ulcers, hepatic coma, kidney stone formation, and many others. In recent years, scientists have devoted considerable efforts to the quest for efficient urease inhibitors. In the pharmaceutical chemistry, the thiourea skeleton plays a vital role. Thus, the present work focused on the development and discovery of novel urease inhibitors and reported the synthesis of a set of 1-aroyl-3-[3-chloro-2-methylphenyl] thiourea hybrids with aliphatic and aromatic side chains 4a–j. The compounds were characterized by different analytical techniques including FT-IR, 1H-NMR, and 13C-NMR, and were evaluated for in-vitro enzyme inhibitory activity against jack bean urease (JBU), where they were found to be potent anti-urease inhibitors and the inhibitory activity IC50 was found in the range of 0.0019 ± 0.0011 to 0.0532 ± 0.9951 μM as compared to the s...
The crystal structure of N-((4-acetylphenyl)carbamothioyl)pivalamide (3) was synthesized by inert... more The crystal structure of N-((4-acetylphenyl)carbamothioyl)pivalamide (3) was synthesized by inert refluxing pivaloyl isothiocyanate (2) and 4-aminoacetophenone in dry acetone. The spectroscopic characterization (1H-NMR, 13CNMR, FT-IR) and single crystal assays determined the structure of synthesized compound (3). Systematic experimental and theoretical studies were conducted to determine the molecular characteristics of the synthesized crystal. The biological examination of (3) was conducted against a variety of enzymes i.e., acetyl cholinesterase (AChE), butyl cholinesterase (BChE), alpha amylase, and urease enzyme were evaluated. The crystal exhibited approximately 85% enzyme inhibition activity against BChE and AChE, but only 73.8 % and 57.9% inhibition activity against urease and alpha amylase was observed respectively. The theoretical calculations were conducted using density functional theory studies (DFTs) with the 6–31G (d, p) basis set and B3LYP functional correlation. The ...
Thiazole derivatives are known inhibitors of alkaline phosphatase, but various side effects have ... more Thiazole derivatives are known inhibitors of alkaline phosphatase, but various side effects have reduced their curative efficacy. Conversely, compounds bearing azomethine linkage display a broad spectrum of biological applications. Therefore, combining the two scaffolds in a single structural unit should result in joint beneficial effects of both. A new series of azomethine-clubbed thiazoles (3a-i) was synthesized and appraised for their inhibitory potential against human tissue non-specific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). Compounds 3c and 3f were found to be most potent compounds toward h-TNAP with IC50 values of 0.15 ± 0.01 and 0.50 ± 0.01 µM, respectively, whereas 3a and 3f exhibited maximum potency for h-IAP with IC50 value of 2.59 ± 0.04 and 2.56 ± 0.02 µM, respectively. Molecular docking studies were also performed to find the type of binding interaction between potential inhibitor and active sites of enzymes. The enzymes inhibition kinetics studies were carried out to define the mechanism of enzyme inhibition. The current study leads to discovery of some potent inhibitors of alkaline phosphatase that is promising toward identification of compounds with druggable properties.
Abstract Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles ( 5a–m ) has been describ... more Abstract Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles ( 5a–m ) has been described by reacting hydrazine-1-carbothioamides ( 3a–k ) with α -chloro- or bromo-acetophenones ( 4a–d ) in refluxing ethanol in good to excellent yields (65–86%). Structural confirmation was based upon spectroscopic techniques such as 1 H-NMR, 13 C-NMR, FT-IR and mass spectrometry. The biological application of these motifs has been demonstrated in terms of their strong urease inhibition activity. The results of in vitro study revealed that all the compounds are the potent inhibitors of urease. The IC 50 (ranging in between 110 and 440 nM) values were higher as compared to that of standard, i.e., thiourea (IC 50 = 490 ± 10 nM). The synthesized compounds were docked at the active sites of the Jack bean urease enzyme in order to explore the possible binding interactions of enzyme–ligand complexes; the results reinforced the in vitro biological activity results. Graphic abstract
The present microreview covers recent advances in the metal-free synthesis of isocoumarin derivat... more The present microreview covers recent advances in the metal-free synthesis of isocoumarin derivatives.
The presence of heterocycles and heteroaromatics as ubiquitous components in a diverse variety of... more The presence of heterocycles and heteroaromatics as ubiquitous components in a diverse variety of synthetic drugs, biologically active molecules, and natural products has inspired the researchers to develop new strategies and technologies for their easy accessibility. Among them, six membered nitrogenous heterocycles gained immense interest, and significant efforts have been made to the development of synthetic strategies which could lead to the discovery of architecturally complex and diverse molecules with high efficiency, low cost, less organic waste and shorter reaction time. Access to such systems by one-pot multi-component approach with inherent advantages of step-economy, operational simplicity, synthetic efficiency, and environmental compatibility is particularly attractive. The current review article highlights the recent developments in the synthesis of six membered nitrogen-containing heterocyclic scaffolds through one-pot multi-component assembly approach.
ABSTRACT Design and synthesis of some new thermally stable polyurethane/polyacrylate blend resins... more ABSTRACT Design and synthesis of some new thermally stable polyurethane/polyacrylate blend resins with high gloss and excellent chemical resistivity has been accomplished. Thus, polyurethane was synthesized from polyethylene glycol (PEG) and hexamethylene diisocyanate (HDI) using the conventional prepolymer method. The double bond functionality is introduced by blocking the prepolymer isocyanate groups with acrylamide so as to utilize acrylic acid as a chain extender to make the resin water dispersible. Polyacrylates are prepared by free radical (emulsion seed) polymerization of methylmethacrylate (MMA), 2-ethylhexylacrylate (2EHA), butylacrylate (BA) and acrylic acid using potassium persulfate (KPS) as an initiator. The morphology of polyurethane and polyacrylate is investigated using FTIR spectroscopy and the thermal stability by TGA. The luster of resin is checked by novo gloss meter. Chemical resistivity of the resin films is determined by immersing the films in different solvents. The rationale of current work was to synthesize some high gloss blend resins from some commonly available monomers, having excellent properties suitable for commercial applications.
The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represents a potential therapeutic ... more The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represents a potential therapeutic target. Specially, a variety of alterations in the ALK gene including mutations, overexpression, amplification, translocations and structural rearrangements, are involved in human cancer tumorigenesis. The second-generation ALK inhibitor CH5424802 (development code: AF802; Chugai Pharmaceutical, a subsidiary of Roche) achieves tumor regression with excellent tolerance and shows promising efficacy in patients with ALK-positive non-small cell lung cancer. CH5424802 shows good kinase selectivity, has a promising pharmacokinetics profile, and has strong antiproliferative activity in several ALK-driven tumor models. CH5424802 has also shown anti-tumor activity in mouse xenograft studies. Here, we summarize recent advances and the evidence that CH5424802 acts as an ALK inhibitor. We also discuss its potential for further development as an anticancer drug in clinical trials.
A variety of 5-(2H-tetrazol-5-yl)-4-thioxo-2-(substituted phenyl)-4,5-dihydro-1,3-oxazin-6-ones (... more A variety of 5-(2H-tetrazol-5-yl)-4-thioxo-2-(substituted phenyl)-4,5-dihydro-1,3-oxazin-6-ones (3a-k) have been synthesized from 1,3-oxazine-5-carbonitriles (2a-k). The protocol represents an efficient, facile and novel route from easily available precursors to unprecedented structures that share 1,3-oxazine and tetrazole motifs of utmost value. All the synthesized compounds (3a-k) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3-oxazine-tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2-bromophenyl moiety was the most potent among the series with IC value 0.0371 ± 0.0018 μM as compared to the reference kojic acid (IC = 16.832 ± 0.73 μM). Inhibitory kinetics showed that compound 3d behaves as a competitive inhibitor. The molecular docking analysis was performed against target protein to investigate the binding mode. Moreover, compounds 3j and 3k displayed superior DPPH ra...
The tropylium ion is a non-benzenoid aromatic species that works as a catalyst. This chemical ent... more The tropylium ion is a non-benzenoid aromatic species that works as a catalyst. This chemical entity brings about a large number of organic transformations, such as hydroboration reactions, ring contraction, the trapping of enolates, oxidative functionalization, metathesis, insertion, acetalization, and trans-acetalization reactions. The tropylium ion also functions as a coupling reagent in synthetic reactions. This cation’s versatility can be seen in its role in the synthesis of macrocyclic compounds and cage structures. Bearing a charge, the tropylium ion is more prone to nucleophilic/electrophilic reactions than neutral benzenoid equivalents. This ability enables it to assist in a variety of chemical reactions. The primary purpose of using tropylium ions in organic reactions is to replace transition metals in catalysis chemistry. It outperforms transition-metal catalysts in terms of its yield, moderate conditions, non-toxic byproducts, functional group tolerance, selectivity, and...
A series of hydrazine-1-carbothioamides derivatives (3a–3j) were synthesized and analyzed for inh... more A series of hydrazine-1-carbothioamides derivatives (3a–3j) were synthesized and analyzed for inhibitory potential towards bovine carbonic anhydrase II (b-CA II) and 15-lipoxygenase (15-LOX). Interestingly, four derivatives, 3b, 3d, 3g, and 3j, were found to be selective inhibitors of CA II, while other derivatives exhibited CA II and 15-LOX inhibition. In silico studies of the most potent inhibitors of both b-CA II and 15-LOX were carried out to find the possible binding mode of compounds in their active site. Furthermore, MD simulation results confirmed that these ligands are stably bound to the two targets, while the binding energy further confirmed the inhibitory effects of the 3h compound. As these compounds may have a role in particular diseases, the reported compounds are of great relevance for future applications in the field of medicinal chemistry.
The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-me... more The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1H-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N–H ⋯ S and C–H ⋯ O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R22 (8) and R22 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⋯ H (59.5%), H ⋯ S/S ⋯ H (16.1%), and H ⋯ C/C ⋯ H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density fun...
The current study focused on the laboratory approach in conjunction with computational methods fo... more The current study focused on the laboratory approach in conjunction with computational methods for the synthesis and bioactivity assessment of unique 2-tetradecanoylimino-3-aryl-4-methyl-1,3-thiazolines (2a–2k). Processes included cyclizing 1-aroyl-3-arylthioureas with propan-2-one in the presence of trimethylamine and bromine. By using spectroscopic techniques and elemental analyses, structures were elucidated. To assess the electronic properties, density functional theory (DFT) calculations were made, while binding interactions of synthesized derivatives were studied by the molecular docking tool. Promising results were found during the evaluation of bioactivity of synthesized compounds against alkaline phosphatase. The drug likeliness score, an indicator used for any chemical entity posing as a drug, was within acceptable limits. The data suggested that most of the derivatives were potent inhibitors of alkaline phosphatase, which in turn may act as lead molecules to synthesize de...
Urease is an amidohydrolase enzyme that is responsible for fatal morbidities in the human body, s... more Urease is an amidohydrolase enzyme that is responsible for fatal morbidities in the human body, such as catheter encrustation, encephalopathy, peptic ulcers, hepatic coma, kidney stone formation, and many others. In recent years, scientists have devoted considerable efforts to the quest for efficient urease inhibitors. In the pharmaceutical chemistry, the thiourea skeleton plays a vital role. Thus, the present work focused on the development and discovery of novel urease inhibitors and reported the synthesis of a set of 1-aroyl-3-[3-chloro-2-methylphenyl] thiourea hybrids with aliphatic and aromatic side chains 4a–j. The compounds were characterized by different analytical techniques including FT-IR, 1H-NMR, and 13C-NMR, and were evaluated for in-vitro enzyme inhibitory activity against jack bean urease (JBU), where they were found to be potent anti-urease inhibitors and the inhibitory activity IC50 was found in the range of 0.0019 ± 0.0011 to 0.0532 ± 0.9951 μM as compared to the s...
The crystal structure of N-((4-acetylphenyl)carbamothioyl)pivalamide (3) was synthesized by inert... more The crystal structure of N-((4-acetylphenyl)carbamothioyl)pivalamide (3) was synthesized by inert refluxing pivaloyl isothiocyanate (2) and 4-aminoacetophenone in dry acetone. The spectroscopic characterization (1H-NMR, 13CNMR, FT-IR) and single crystal assays determined the structure of synthesized compound (3). Systematic experimental and theoretical studies were conducted to determine the molecular characteristics of the synthesized crystal. The biological examination of (3) was conducted against a variety of enzymes i.e., acetyl cholinesterase (AChE), butyl cholinesterase (BChE), alpha amylase, and urease enzyme were evaluated. The crystal exhibited approximately 85% enzyme inhibition activity against BChE and AChE, but only 73.8 % and 57.9% inhibition activity against urease and alpha amylase was observed respectively. The theoretical calculations were conducted using density functional theory studies (DFTs) with the 6–31G (d, p) basis set and B3LYP functional correlation. The ...
Thiazole derivatives are known inhibitors of alkaline phosphatase, but various side effects have ... more Thiazole derivatives are known inhibitors of alkaline phosphatase, but various side effects have reduced their curative efficacy. Conversely, compounds bearing azomethine linkage display a broad spectrum of biological applications. Therefore, combining the two scaffolds in a single structural unit should result in joint beneficial effects of both. A new series of azomethine-clubbed thiazoles (3a-i) was synthesized and appraised for their inhibitory potential against human tissue non-specific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). Compounds 3c and 3f were found to be most potent compounds toward h-TNAP with IC50 values of 0.15 ± 0.01 and 0.50 ± 0.01 µM, respectively, whereas 3a and 3f exhibited maximum potency for h-IAP with IC50 value of 2.59 ± 0.04 and 2.56 ± 0.02 µM, respectively. Molecular docking studies were also performed to find the type of binding interaction between potential inhibitor and active sites of enzymes. The enzymes inhibition kinetics studies were carried out to define the mechanism of enzyme inhibition. The current study leads to discovery of some potent inhibitors of alkaline phosphatase that is promising toward identification of compounds with druggable properties.
Abstract Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles ( 5a–m ) has been describ... more Abstract Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles ( 5a–m ) has been described by reacting hydrazine-1-carbothioamides ( 3a–k ) with α -chloro- or bromo-acetophenones ( 4a–d ) in refluxing ethanol in good to excellent yields (65–86%). Structural confirmation was based upon spectroscopic techniques such as 1 H-NMR, 13 C-NMR, FT-IR and mass spectrometry. The biological application of these motifs has been demonstrated in terms of their strong urease inhibition activity. The results of in vitro study revealed that all the compounds are the potent inhibitors of urease. The IC 50 (ranging in between 110 and 440 nM) values were higher as compared to that of standard, i.e., thiourea (IC 50 = 490 ± 10 nM). The synthesized compounds were docked at the active sites of the Jack bean urease enzyme in order to explore the possible binding interactions of enzyme–ligand complexes; the results reinforced the in vitro biological activity results. Graphic abstract
The present microreview covers recent advances in the metal-free synthesis of isocoumarin derivat... more The present microreview covers recent advances in the metal-free synthesis of isocoumarin derivatives.
The presence of heterocycles and heteroaromatics as ubiquitous components in a diverse variety of... more The presence of heterocycles and heteroaromatics as ubiquitous components in a diverse variety of synthetic drugs, biologically active molecules, and natural products has inspired the researchers to develop new strategies and technologies for their easy accessibility. Among them, six membered nitrogenous heterocycles gained immense interest, and significant efforts have been made to the development of synthetic strategies which could lead to the discovery of architecturally complex and diverse molecules with high efficiency, low cost, less organic waste and shorter reaction time. Access to such systems by one-pot multi-component approach with inherent advantages of step-economy, operational simplicity, synthetic efficiency, and environmental compatibility is particularly attractive. The current review article highlights the recent developments in the synthesis of six membered nitrogen-containing heterocyclic scaffolds through one-pot multi-component assembly approach.
ABSTRACT Design and synthesis of some new thermally stable polyurethane/polyacrylate blend resins... more ABSTRACT Design and synthesis of some new thermally stable polyurethane/polyacrylate blend resins with high gloss and excellent chemical resistivity has been accomplished. Thus, polyurethane was synthesized from polyethylene glycol (PEG) and hexamethylene diisocyanate (HDI) using the conventional prepolymer method. The double bond functionality is introduced by blocking the prepolymer isocyanate groups with acrylamide so as to utilize acrylic acid as a chain extender to make the resin water dispersible. Polyacrylates are prepared by free radical (emulsion seed) polymerization of methylmethacrylate (MMA), 2-ethylhexylacrylate (2EHA), butylacrylate (BA) and acrylic acid using potassium persulfate (KPS) as an initiator. The morphology of polyurethane and polyacrylate is investigated using FTIR spectroscopy and the thermal stability by TGA. The luster of resin is checked by novo gloss meter. Chemical resistivity of the resin films is determined by immersing the films in different solvents. The rationale of current work was to synthesize some high gloss blend resins from some commonly available monomers, having excellent properties suitable for commercial applications.
The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represents a potential therapeutic ... more The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represents a potential therapeutic target. Specially, a variety of alterations in the ALK gene including mutations, overexpression, amplification, translocations and structural rearrangements, are involved in human cancer tumorigenesis. The second-generation ALK inhibitor CH5424802 (development code: AF802; Chugai Pharmaceutical, a subsidiary of Roche) achieves tumor regression with excellent tolerance and shows promising efficacy in patients with ALK-positive non-small cell lung cancer. CH5424802 shows good kinase selectivity, has a promising pharmacokinetics profile, and has strong antiproliferative activity in several ALK-driven tumor models. CH5424802 has also shown anti-tumor activity in mouse xenograft studies. Here, we summarize recent advances and the evidence that CH5424802 acts as an ALK inhibitor. We also discuss its potential for further development as an anticancer drug in clinical trials.
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