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Current Medicinal Chemistry, 2017, 24, 2392-2412

REVIEW ARTICLE
eISSN: 1875-533X ISSN: 0929-8673

Current
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Medicinal
Targeting Malassezia species for Novel Synthetic and Natural Chemistry

Antidandruff Agents The

International
Journal for
Timely In-depth
Reviews
in Medicinal
Chemistry

BENTHAM
SCIENCE

Letizia Angiolellaa, Simone Carradorib,*, Cristina Maccallinib, Gustavo Giusianoc and

Claudiu T. Supurand

a
Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.le A. Moro 5, 00185
Rome, Italy; b Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31,
66100 Chieti, Italy; cDepartamento de Micología, Instituto de Medicina Regional, Facultad de Medicina,
Universidad Nacional del Nordeste, CONICET, Resistencia, Argentina; dNeurofarba Dept., Section of Phar-
maceutical and Nutriceutical Sciences, Università degli Studi di Firenze, via U. Schiff 6, 50019 Sesto Fioren-
tino (Florence), Italy

Abstract: Malassezia spp. are lipophilic yeasts not only present in the normal skin micro-
flora, but also responsible of skin-related diseases (pityriasis versicolor, seborrheic/atopic
dermatitis and dandruff) as well as systemic fungal infections in humans and animals. Their
treatment and eradication are mainly based on old azole drugs, which are characterized by
ARTICLE HISTORY poor compliance, unpredictable clinical efficacy, emerging resistance and several side ef-
Current Medicinal Chemistry

Received: October 24, 2016 fects. These drawbacks have prompted the research toward novel synthetic and natural de-
Revised: February 16, 2017
Accepted: March 21, 2017 rivatives/nanomaterials targeting other pivotal enzymes/pathways such as carbonic anhy-
DOI:
drase (MgCA) and lipases, alone or in combination, in order to improve the eradication rate
10.2174/0929867324666170404110631 of this fungus. This review accomplished an update on this important topic dealing with the
latest discoveries of synthetic scaffolds and natural products for the treatment of
Malassezia spp.-related diseases, thus suggesting new opportunities to design innovative
and alternative anti-dandruff drugs.
Keywords: Azoles, carbonic anhydrase inhibitors, dandruff, lipase inhibitors, Malassezia spp., natural inhibitors.

1. INTRODUCTION detected species in human skin [3]. Conversely, M.

pachydermatis, a zoophilic species, is known to cause
Malassezia species are ubiquitous single-celled
the majority of external otitis and seborrheic dermatitis
basidiomycetous yeasts, which are common elements
cases in dogs [4]. Interestingly, there is evidence indi-
of fungal microbiota of animal and human skin. Some
cating its role also in systemic infections in hospital-
species could produce hyphae when they become
ized and parenterally fed human infants [5, 6].
pathogenic. They are divided into 15 species of which
14 are lipid dependent. This genus includes M. cu- Studied by electron microscopy, Malassezia cells
niculi, M. nana, M. slooffiae, M. caprae, M. pachyder- structurally show a thick and multilaminar cell wall,
matis, M. globosa, M. sympodialis, M. equina, M. der- composed of chitin and an extremely high level of lip-
matis, M. furfur, M. japonica, M. obtusa, M. restricta, ids (15-20%, w/w) greater than Candida albicans and
M. yamatoensis [1] and the recently discovered M. Saccharomyces cerevisiae, with a characteristic invagi-
arunalukei [2]. M. sympodialis, M. furfur, M. slooffiae, nation, a cell membrane, and vital organelles [7, 8]. Its
M. restricta and M. globosa are the most commonly cell surface hydrophobicity (CSH) has been recognized
as the main pathogenic factor contributing to drug re-
*Address correspondence to this author at the Department of Phar- sistance, reduction of the immune susceptibility, and
macy, “G. d’Annunzio” University of Chieti-Pescara, Via dei development of inflammation [9].
Vestini 31, 66100 Chieti, Italy; Tel: +39 0871 3554583;
E-mail: simone.carradori@unich.it

1875-533X/17 $58.00+.00 © 2017 Bentham Science Publishers

Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2393

Recently, some authors elucidated the polysaccha- fur is also able to form biofilm in vitro [18] and in vivo
ride composition in the cell wall of M. restricta, deter- as protective mechanism for evasion of immune sur-
mining its unusual and unique structure and alkali- veillance and as barrier against antimicrobial agents.
resistance due to a specific content of 5% chitin, 20% Conversely, M. globosa and M. restricta secrete several
chitosan, 5% β-(1-3)-glucan, and 70% β-(1-6)-glucan lipases that can be categorized as Family Lipase 3 and
[10]. The hydrophobic organization makes Malassezia Family LIP 2, both responsible of the production of
spp. to proliferate in a niche where lipid rich sebum is fatty acids endowed with inflammatory effects [19-24].
abundant (scalp and other seborrheic regions) in order The pathogenicity could be also correlated with host
to compensate their lipid dependence based on a dys- hormonal, metabolic or immunological disorders and
regulated synthesis of myristic acid [11], which is predisposing environmental circumstances (tempera-
compensated by the over-activity/expression of hydro- ture and humidity, and genetic susceptibility) that alter
lases for the production of medium-length or long- the cutaneous lipid profile. Nowadays, Malassezia spp.
chain fatty acids [12]. Except M. pachydermatis, all were shown to be the etiological agents of a large num-
Malassezia species require fatty acids to survive as ber of superficial skin diseases including pityriasis ver-
their carbon source. Another characteristic of the cell sicolor (PV) [25-27], Malassezia folliculitis [28], seb-
wall of Malassezia is the Mala s 1 protein exposed on orrheic dermatitis (SD) [29-31], dandruff [32-35], and
cell surface, being a major allergen in Malassezia- atopic dermatitis (AD) [36-39]. Until recently, only M.
related disorders of the skin [13, 14]. Recent studies furfur has been thought to be responsible for the onset
demonstrated that Malassezia spp. could directly of dandruff. However, the scalp specific species M.
stimulate the production of inflammatory cytokines, globosa and M. restricta have recently been found to
chemokines and adhesion molecules in human epider- be the most probable causative agents [40]. Finally,
mal keratinocytes [8, 15]. Mishra et al. reported that Malassezia-related fungaemia, associated to cardiac
this host immune activation is also characterized by the and pulmonary infections, usually occurs in young pa-
stimulation of T-cell reactivity and IgE production tients through the not correct use of catheters.
[16]. A peculiar aspect of Malassezia spp. is its repro-
duction occurring by monopolar or unipolar budding. 2. LITERATURE SURVEY FOR THE TREAT-
The extruded bud is separated by a septum from the MENT OF MALASSEZIA SPP.
mother cell and successive scars form a small collar
(collarette) (Fig. 1) [12]. These features can differenti- Current treatment of dandruff/seborrheic dermatitis
ate Malassezia from other yeasts. takes advantage of a limited arsenal of anti-fungal
drugs such as ketoconazole (KTZ), coal tar, zinc py-
rithione, piroctone olamine, triclosan, selenium sulfide
and lipase inhibitors. In addition to azole derivatives,
the treatment options for M. pachydermatis infection
also include chlorhexidine (Fig. 2). Shampoos and
other cosmetic formulations (lotions and conditioners),
containing active ingredients such as ketoconazole
(1%), miconazole (2%), chlorhexidine (2-4%) or com-
binations of them, are commonly used for Malassezia
dermatitis treatment. Disregarding its efficacy against
Malassezia-related infections, ketoconazole is known
to have low clinical safety.
As a standardized protocol to assess the antifungal
Fig. (1). Reproduction of Malassezia by budding. efficacy against Malassezia spp. has not been disclosed
by Clinical and Laboratory Standards Institute (CLSI)
Another class of important enzymes found in M. and the European Committee on Antimicrobial Suscep-
furfur is tryptophan aminotransferases, responsible of tibility Testing (EUCAST) [3], the data should be con-
the conversion of L-tryptophan to different indolepyru- sidered with caution because of the absence of clinical
vate metabolites [11]. Malassezin is a tryptophan me- breakpoints. In this regard, the epidemiological cut-off
tabolite and induces apoptosis in human melanocytes values (ECVs) are important to discriminate between
by means of a direct binding to the aryl hydrocarbon susceptible and resistant isolates. Further investiga-
receptor (AhR) [17]. As other microorganisms, M. fur- tions and studies are crucial for correlating in vitro
2394 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

-O
S-
N+ Cl Cl
Zn+2 Ac N N O
N+ O
O - S-
H O
Zinc pyrithione N
Ketoconazole (KTZ)
N
Cl
NH NH
H H H
N N N SeS
N N N
H H H
NH NH
Cl
Chlorhexidine Selenium sulfide

Cl OH
O
N O
. H 2N
OH

Cl Cl OH

Triclosan Piroctone olamine

Fig. (2). Common arsenal for the treatment of Malassezia-related dandruff.

Cl Cl N
N
N N
N F
OH OH
O
N N N N
N N
Cl F N F N

Cl F F

Miconazole (MCZ) Fluconazole (FLZ) Voriconazole (VOR)

N Cl Cl
N N N O
N O

O H O
N

Itraconazole (ITZ) N

HO N F F
N N N O
N O

O H
N

Posaconazole (POS) N
F
Cl

N F
N O
O
N N O
N O
O
N
N
O
Climbazole (CLZ) Pramiconazole
N N

Fig. (3). Azole compounds tested against Malassezia.

Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2395

Table 1. The most recent data about Malassezia spp. susceptibility to azoles, MIC values and characteristics of the iso-
lated strains.

Strain Azole MICa50 MICa90

Source Further Information References
(n° of Isolates) Drug (µg/mL) (µg/mL)

M. globosa CLZ 0.3125 -

human patients diagnosed
M. restricta CLZ 2.5 - 4-week single-center,
with facial symmetric
open-label split-face [47]
M. sympodialis mild-to-moderate sebor- CLZ 0.3125 - study
rheic dermatitis
M. slooffiae CLZ 1.25 -
FLZ 8 32

M. pachydermatis ITZ 0.008 0.016

dog skin
(62) POS 0.016 0.032
VOR 0.064 0.064
FLZ 64 128

M. furfur human blood and sterile ITZ 0.25 1 epidemiological cut-off

[48]
(60) sites POS 0.25 0.5 values were reported

VOR 1 2
FLZ 128 >128

M. furfur ITZ 0.25 0.5

human skin
(18) POS 0.125 0.25
VOR 2 2

M. pachydermatis KTZ 0.094 0.125

healthy dog skin
(72) ITZ 0.047 0.119
[49]
M. pachydermatis dog skin with atopic der- KTZ 0.33-1.33 1.6-5.2
(110) matitis ITZ 0.27-1.6 3-7.09
FLZ 4 16
ITZ 0.03 0.06
M. furfur human patients with der-
KTZ 0.03 0.06
(39) matological pathologies
VOR 0.06 0.25
MCZ 1 4
FLZ 0.5 2
ITZ 0.03 0.06
M. sympodialis human patients with der-
KTZ 0.03 0.03 [50]
(20) matological pathologies
VOR 0.06 0.06
MCZ 0.25 4
FLZ 0.5 2
ITZ 0.03 0.06
M. globosa human patients with der-
KTZ 0.03 0.03
(14) matological pathologies
VOR 0.03 0.125
MCZ 0.25 2

(Table 1) contd….
2396 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

Strain Azole MICa50 MICa90

Source Further Information References
(n° of Isolates) Drug (µg/mL) (µg/mL)

FLZ 2 4

M. pachydermatis dogs with external otitis ITZ 0.125 0.5 fluconazole-sensitive

(30) and dermatitis KTZ 0.03 0.06 strains

VOR 0.25 2
[51]
FLZ 64 128

M. pachydermatis dogs with external otitis ITZ 16 64 fluconazole-resistant

(30) and dermatitis KTZ 16 32 strains

VOR 32 64
a
MIC= Minimum Inhibitory Concentration

data with clinical outcomes since the current defence mechanism has been shown to be the drug ef-
published values do not provide definitive conclu- flux pumps [52].
sions. Pramiconazole is a broad-spectrum triazole antifun-
gal (Fig. 3) more active than ketoconazole against
2.1. Azoles and their Derivatives
pathogenic Candida spp., dermatophytes, and 29
Several past studies have demonstrated the sensibil- strains of Malassezia spp. (MIC <1 µg/mL) [53].
ity/resistance of Malassezia spp. isolated from humans Moreover, it was tested orally for efficacy and toler-
or animals to the treatment with azoles (Fig. 3) [41-45]. ability in the treatment of seborrheic dermatitis [54]
Moreover, ketoconazole and pramiconazole were and pityriasis versicolor (randomized, multicenter,
shown to reduce, in a dose dependent manner, the pro- double-blind, placebo-controlled, 28-day, dose-finding
duction of hyphae in M. furfur and sympodialis [46]. study) [55]. A statistically significant dose-dependent
To gain new insights about the efficacy of this class effect was observed and there were no treatment-
of drugs and to establish putative epidemiological cut- related adverse events up to 1 month after treatment
off values (ECVs), several authors focused their efforts onset.
on testing clinical isolates of Malassezia spp. deriving Starting from the promising antifungal activity ob-
from healthy (ecosystem inhabiting the skin) or com- tained with several 2-(substituted phenyl or benzyl)
promised patients (humans or animals as reported in benzoxazoles, and on the basis of the chemical skeleton
Table 1). The Minimum Inhibitory Concentration of malassezin, benzoxazole amides were synthesized
(MIC) was defined as the lowest drug concentration and evaluated against M. furfur using the disc diffusion
without visible growth. MIC50 and MIC90 refer to MIC method as bioisosteres of azole drugs. Ketoconazole
for 50 and 90 % of strains, respectively. was chosen as reference drug (MIC value of 16 µg/mL)
Collectively, azole drugs represent the first choice for comparison (Fig. 4) [17].
for an effective treatment of Malassezia-related infec-
tions. In detail, MICs for fluconazole were usually R1 R2
higher than those observed for other azoles, and it is R3 O O
not considered as a good choice for Malassezia treat- R2 N N R3
NH NH
ment. Conversely, a wide range of MIC values was O O
R1
reported for miconazole, one of the most widely used
topical drugs. The source of isolation was demonstrated 1 R 1= R 2= R 3= H 9 R1= R3= H, R2= C3H6NS2
to affect strain susceptibility because of the statistically 2 R1= R3= H, R2= Cl 10 R1= Cl, R2= H, R3= NO2
3 R1= R3= H, R2= NO2 11 R1= R2= H, R3= CH3
significative differences registered in their MIC values. 4 R1= R3= H, R2= OCH3 12 R1= R2= H, R3= OCH3
5 R1= R2= H, R3= CH3
Surprisingly, the reported ECV values for azole 6 R1= CH3, R2= R3= H
drugs suggest that in M. pachydermatis and M. furfur 7 R1= R3= H, R2= COOH
different resistance mechanisms could be achieved, 8 R1= CF3, R2= R3= H

because M. pachydermatis displayed cross-resistance Fig. (4). Benzoxazole amide derivatives.

among the azoles, differing from M. furfur. The main
Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2397

Despite the substitution pattern, only few com- In order to study the susceptibility variations to this
pounds displayed a slight inhibitory activity, and infe- agent, 31 strains of M. furfur, restricta, and globosa
rior to ketoconazole (the unsubstituted compound 1 were inhibited with MIC values spanning from <0.03
with MIC value of 350 µg/mL). The 4-substitued ana- to 32.0 µg/mL, 0.06 to 4.0 µg/mL and 0.06 to 16.0
logs with nitro, methyl or methoxy groups (10-12) did µg/mL, respectively. Susceptibility results of the
not exert inhibitory activity, (MIC values >1000 Malassezia spp. for terbinafine were comparable to
µg/mL). In addition, they presented strong cytotoxic those obtained using LNA (Leeming-Notman agar me-
activity at 10 µg/mL against an immortalized human dium). Only M. sympodialis isolates were generally
cell line (HepG2). susceptible to terbinafine (MIC≤0.25 µg/mL).

2.2. Amphotericin B 2.4. Selective M. globosa Carbonic Anhydrase

(MgCA) Inhibitors and Activators
This well-established antifungal agent (Fig. 5) has
been proposed for the treatment of Malassezia spp. be- Carbonic anhydrases (CAs) are ubiquitous metal-
cause it displayed low and promising MIC50 values loenzymes extensively studied in bacteria, fungi, proto-
against several clinical isolates of M. furfur, sympo- zoa as well as in human tissues. Their physiological
dialis and globosa, disregarding the experimental pro- role involves vital and pathological processes [59] and
cedure used (broth microdilution and E-test), and the depending on the structure and the type of the ion pre-
source of isolation [50, 56, 57]. sent in the active site they are usually divided into
seven families (α-, β-, γ-, δ, ζ-, η-, and recently discov-
OH ered θ-CAs), one of which (β class) has been well char-
OH
HO O OH
acterized in Malassezia globosa [60, 61]. The presence
HO O OH OH OH OH O of this versatile enzyme has been related to the uncon-
COOH
trolled growth and the induction of marked virulence in
this fungus. Hence, the interference with the crucial
O O activities regulated by CAs in microorganisms induces
dysregulation of pH homeostasis, adenylyl cyclase ac-
HO OH
NH2
tivity, both sexual development and reproduction in
Amphotericin B
filamentous ascomycetes as well as impairment of bio-
synthetic reactions mediated by acetyl-CoA carboxy-
Fig. (5). Structure of Amphotericin B. lase, pyruvate carboxylase, phosphoribosylaminoimi-
dazole carboxylase and carbamoyl phosphate synthase,
MIC50 values ranging from 0.125 to 0.5 µg/mL were leading to significant antifungal effect both in vivo and
also registered for this drug against Malassezia isolates in vitro [62]. Taking into consideration the emergence
considered as resistant by the M27-A3 document (like of resistant strains as a serious healthcare problem
reported for Candida species), but no breakpoints for worldwide, the design of selective inhibitors of these
categorizing these yeasts as resistant to AMB were dis- fungal isoforms could open new scenarios for obtaining
closed. new anti-Malassezia agents endowed with a novel
mechanism of action, since the β-CAs are not present
2.3. Terbinafine in mammals (encoding only for α-CAs).
Terbinafine (Fig. 6) is a fungicidal drug belonging More in detail, Malassezia globosa has been re-
to the class of allylamines [42, 58]. cently studied for the presence of its specific β-CAs by
Supuran’s group [63, 64]. This isozyme (MgCA) is
endowed with outstanding enzymatic activity for the
N
catalysis of CO2 hydration and utilizes, in its long ac-
tive site, one histidine, one aspartate (in the “closed
active site”), and two cysteines for the coordination of
the Zn(II), or one histidine, two cysteines, and a water
molecule/hydroxide ion in the “opened active site”.

Terbinafine
A preliminary inhibition data analysis with inor-
ganic/organic anions and other small Zn-coordinating
Fig. (6). Structure of terbinafine. molecules provided important structural information
2398 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

Table 2. Ki values against Malassezia globosa CA and MICs obtained with new inhibitors and clinically used com-
pounds.

MIC (µg/mL)
Compound Ki (nM) MgCA
M. furfur M. dermatis CBS M. pachydermatis M. globosa CBS
CBS 9569 9145 CBS 6536 7966

1 9800 640 640 >640 640

2 245 80 160 10 80
3 152 - - - -
4 6740 640 320 320 160
5 174 320 160 160 160
6 79 640 640 640 320
7 116 - - - -
8 123 - - - -
9 349 - - - -
10 543 - - - -
11 90 >640 >640 >640 320
12 92 640 640 640 640
13 79000 - - - -
14 85000 - - - -
15 236 - - - -
16 104 - - - -
17 63 - - - -
18 68 - - - -
19 35000 - - - -
20 234 - - - -
21 118 - - - -
22 94 >640 >640 640 640
23 4530 160 >640 160 320
24 2560 - - - -
25 3100 - - - -
26 650 320 320 320 320
27 374 - - - -
28 413 - - - -
29 660 - - - -
30 2750 - - - -
31 710 - - - -
32 220 - - - -
33 8090 - - - -
34 3490 - - - -
35 670 - - - -
(Table 2) contd….
Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2399

MIC (µg/mL)
Compound Ki (nM) MgCA
M. furfur M. dermatis CBS M. pachydermatis M. globosa CBS
CBS 9569 9145 CBS 6536 7966

36 4500 - - - -
acetazolamide (AAZ) 76000 640 320 640 320
methazolamide (MZA) 74550 - - - -
ethoxzolamide (EZA) 38000 - - - -
dichlorphenamide (DCP) 346 >640 >640 >640 320
dorzolamide (DZA) 79000 - - - -
brinzolamide (BRZ) 84000 - - - -
benzolamide (BZA) 482 - - - -
topiramate
1460 - - - -
(TPM)
sulpiride
320 - - - -
(SLP)
indisulam
113 - - - -
(IND)
zonisamide
7650 - - - -
(ZNS)
celecoxib
34800 - - - -
(CLX)
valdecoxib
31500 - - - -
(VLX)

about the requirements for inhibiting this enzyme [65]. (i) Many compounds, especially the heterocyclic sul-
A large panel of anions (perchlorate, (seleno)cyanide, fonamide derivatives, were endowed with a fair
nitrate, halides, azide, carbonate, perrhenate, sulfate, MgCA inhibition (Kis range = 2.56-76 µM);
nitrite, stannate, bisulfite, peroxydisulfate, selenate, (ii) Some of them displayed a very potent enzyme in-
perosmate, diphosphate, tellurate, hydrogen sulfide, hibition in vitro (Kis range = 104-650 nM). These
divanadate, fluorosulfonate, hexafluorophosphate, tri- comprehended 4-substituted benzenesulfona-
flate, tetraborate, trithiocarbonate, (thio)cyanate, and mides, halogenosulfanilamides, aminobenzola-
tetrafluoroborate), usually acting as weak inhibitors in mides, as well as DCP, BZA, SLP and IND;
other CAs, was not active against this fungal isoform (iii) Few compounds (6, 11, 12, 17, 18, 22), belonging
(millimolar range). Among the most potent inhibitors to benzenesulfonamide or 1,3-disulfonamide scaf-
(sulfamate, sulfamide, phenylarsonic and phenylbo- folds, had Ki in the range of 63-94 nM.
ronic acids), bicarbonate (Ki = 590 µM) and dieth-
yldithiocarbamate (Ki = 300 µM) were quite unex- Compounds 29-36 were obtained by direct N-
pected and comparable with the reference drug, aceta- nitration of the sulfonamide group, trying to evaluate
zolamide, because the former is obviously also a sub- the impact on biological activity of a nitro substituent,
that could improve the interaction with the Zn(II) in the
strate/reaction product of the CA-mediated physiologi-
active site reinforcing the acidity of SO2 NH moiety
cal reaction. Conversely, Table 2 collects the MgCA
[66]. The fungal isoform was efficiently blocked by
inhibition data with a series of well known and clini-
these N-nitro sulfonamides functionalized with small
cally used hCA inhibitors (Fig. 7) [63].
hydrophilic substituents at para position of the aryl
Other sulfonamide derivatives 1-36 (Fig. 8) were ring, with Kis ranging between 0.22 and 8.09 µM.
also included in this study. These results were better than those of the reference
These following structure-activity relationships sulfonamide drug AAZ (Ki of 74.0 µM). Moreover,
(SARs) can be detected: these N-nitro sulfonamides presented a selective inhibi-
tion of MgCA with respect to other human (hCA
2400 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

N N O N N N SO2NH2
O SO2NH2 SO2NH2 SO2NH2
S N S S
N EtO
H
Cl SO2NH2
MZA EZA Cl
AAZ
DCP
NHEt NHEt
N N
SO2NH2 SO2NH2 O O SO2NH2
S MeO N S S S
S S N
H
O O O O

DZA BRZ BZA

SO2NH2 OMe O
O
O O O O
N
H S
O N Cl N
O H
O NH
SO2NH2 SO2NH2

TPM SLP IND

SO2NH2 SO2NH2
SO2NH2

N
O
N
N
O N
F 3C

ZNS CLX VLX

Fig. (7). Sulfonamide drugs tested as Malassezia globosa carbonic anhydrase inhibitors.

II) and pathogenic fungal β-CAs (high selectivity de- MgCA enzyme showed affinity for bortezomib with Ki
gree), and MIC values against four strains of of 3.24 µM. Phenylboronic acid (Fig. 9), instead, be-
Malassezia spp. in vitro for the most potent derivatives haved as rather a weak inhibitor of MgCA, with Ki of
were also registered (Table 2). Moreover, compound 6, 89 µM. These data suggest that aliphatic boronic acids
with Ki of 79 nM against MgCA in vitro and medium could be in detail explored in order to find new potent
MIC values, was chosen for the treatment of a murine MgCA inhibitors.
model of dandruff/Malassezia infection; 67% of the Another promising scaffold of dithiocarbamates, ob-
mice demonstrated clinical improvement. These results tained from primary and secondary amines, was re-
demonstrated that the inhibition of this enzyme cently proposed (Fig. 9). They were more potent than
(MgCA) could correlate with in vitro and in vivo treat- the reference drug (AAZ) with inhibition constants
ment of Malassezia infections. ranging from 383 to 6235 nM. The aliphatic chain
However, one of the main issues is that these inhibi- length influenced positively the biological activity. Un-
tors are functionalized with primary sulfonamides and fortunately, these derivatives were also strong inhibi-
their isosteres, usually recognized also as potent inhibi- tors of human CAs, because they established a direct
tors of human CAs with the development of side ef- and strong interaction with the zinc ion in the active
fects [67-78]. For this reason, boronic acid derivatives site (a common structural feature in most of CAs), as
(Fig. 9) could behave as alternative chemotypes, as reported by molecular modelling studies [82].
proposed in the very recent literature [79, 80]. The pep- Conversely, following a computational approach per-
tidomimetic boronic acid bortezomib is clinically used formed to suggest new chemotypes for the selective in-
for the therapy of haematological tumours. teraction with this enzyme [83], some MgCA activators
Bortezomib inhibited promisingly both α- and β- (a series of amines and amino acids 1-19, Fig. 10) were
class CAs in the low micromolar range [81]. The proposed to modulate the β-CA catalytic/activation
Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2401

SO2NH2 SO2NH2 SO2NH2 SO2NH2 SO2NH2 SO2NH2 SO2NH2 SO2NH2

NH2

F Cl
NH2 COOH NH2 NH2 NH2
NH2
1 2 3 4 5 6 7 8

SO2NH2 SO2NH2 SO2NH2

SO2NH2 N N N N
F 3C Cl SO2NH2 SO2NH2
H 2N S S
HN
Br I SO2NH2 SO2NH2
NH2 NH2 NH2 NH2

9 10 11 12 13 14

N N H 2N N N N N
O O SO2NH2 SO2NH2 OO SO2NH2
S S S S S
N S N N
H H H
O O
H2N H 2N
15 16 17
SO2NH2 SO2NH2 SO2NH2
Cl N N
HN SO2NH2 SO2NH2
S
N
N OH COOH
OH
NH2
18 19 20 21 22

SO2NH2 SO2NH2 O H O H O H
X X O S N NO2 O S N NO2 O S N NO2
NH2

NH2
Br
NH2
23 X= nothing 26 X= nothing
24 X= O 27 X= O 29 30 31
25 X= NH 28 X= NH

O H O H O H O H
O S N NO2 O S N NO2 O S N NO2 O S N NO2
H 2N S O
O
S
N N
O 2N NH2 HN NO2
N HN OH
NH2
32 33 34 35 36

Fig. (8). Sulfonamide derivatives tested as Malassezia globosa carbonic anhydrase inhibitors.

N O
H B(OH)2
N N
N B(OH)2
H
O

Bortezomib Phenylboronic acid

R= aminoalkane,
hydroxyalkane, R S
cyclic amine,
N
aliphatic chain
R1 S- Na+
R1= H, carbocycle

Dithiocarbamate derivatives
Fig. (9). Boronic acid derivatives and dithiocarbamates as innovative Malassezia globosa carbonic anhydrase inhibitors.
2402 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

O O O O O
H2N H2N H2N H2N H2N
OH OH OH OH OH

OH
NH NH
N
OH OH

1 L-His 1 L-Phe 1 L-DOPA 7 L-Trp 9 L-Tyr

2 D-His 2 D-Phe 2 D-DOPA 8 D-Trp 10 D-Tyr

O
H2N NH2 NH2 HO
OH N NH2

N N
H OH H
OH
NH2

11 12 13 14

OH
HO
NH2 NH2
NH2 X N
N N NH2 HO

15 16 17 X= NH 19
18 X= O
Fig. (10). Activators of Malassezia globosa carbonic anhydrase.

mechanism in Malassezia globosa [84]. Data showed with silver nanoparticles (AgNPs) as antifungal agents,
that L-adrenaline 19 and 1-(2-aminoethyl)piperazine 17 showed enhanced activity against clinically relevant
were potent activators of MgCA, and that compounds fungi. Moreover, these nanoparticles were able of lim-
bearing an amine group were generally more potent iting multidrug resistance and their formulations
activators compared to those functionalized with a car- (antidandruff shampoos) were reported to act as effec-
boxylic acid moiety. tive against M. furfur-related dermal diseases.
AgNPs usually have a broadest spectrum fungicidal
2.5. Bioactive Components and Extracts of Plants
(2012-2017) activity which makes them good candidates to eradi-
cate fungal infection without recurrence. Moreover,
Natural products as source of promising agents silver is reported to enhance the generation of reactive
against Malassezia have been partially reviewed in the oxygen species which in turn degrade the cell mem-
past [85-87]. For this reason, in this paragraph, only brane and to catalyze the denaturation of S-S bridge in
papers published from 2012 were analyzed for an up- the cellular proteins. Several examples are reported in
date on this matter. It emerged the role of specific phy- the literature both incorporating well known drugs or
tocomponents such as saponins, xanthones, flavan-3- new chemical entities/natural substances.
ols, and essential oils to display anti-Malassezia activ-
The antidandruff activity of ketoconazole-coated
ity (Table 3).
silver nanoparticles by disc diffusion method was in-
In addition, some authors screened in silico vestigated against M. furfur. Antidandruff activity
through molecular simulations two phytocomponents (MIC) was the highest with ketoconazole-coated AgNP
(β-Sitosterol and Calceolarioside A, Fig. 11) showing a (0.0135 mg/mL) when compared to ketoconazole alone
potent ability to bind to Mala s 1 [16]. (0.06 mg/mL) or AgNP alone (0.026 mg/mL). Moreo-
ver, they could act synergistically in combination being
2.6. Silver Nanoparticles Ketoconazole active against fungal cell wall and
Drug-nanoparticle hybrid systems have widely been AgNPs against intracellular targets. Thus, AgNPs not
found useful in the enhancement of bioavailability, only act as a better antidandruff agent but could also
bioactivity and stability of clinically used drugs. Sul- reduce the side effects of ketoconazole by reducing its
fonamides, sulfadiazine and sulfamerazine complexed concentration [98].
Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2403

Table 3. Natural products proposed and evaluated for the treatment of Malassezia spp.

Plant Extraction Solvent Antifungal Activity Against Malassezia spp. References

Ricinus communis L. leaves water, chloroform, methanolic extracts exhibited significant activity (8.20 [88]
methanol and petro- mm of inhibition zone), aqueous extracts recorded
leum ether appreciable inhibitory activity (5.74 mm of inhibition
zone) when compared with chloroform (1.66 mm of
inhibition zone) and petroleum ether extracts (inac-
tive) at 500 µg/mL concentration
Asparagus racemosus roots fractioning extraction The inhibitory activity against Malassezia globosa and [89]
with n-hexane, 95% furfur of each extract was influenced positively by its
ethanol, distilled wa- saponin content, but it was always inferior to the ref-
ter, acetone, n-butanol erence drugs (zinc pyrithione and ketoconazole). No
to obtain different putative synergistic effects between A. racemosus
crude and saponin- extracts and zinc pyrithione or ketoconazole were
enriched extracts demonstrated (FIC index <0.5 or >4)
Leaves of Evolvulus alsinoides, ethanol Evolvulus alsinoides exhibited MFC of 0.2 mg/mL [90]
Azadirachta indica, Hibiscus rosa- (ZOI = 6 mm), whereas Azadirachta indica, Lawsonia
sinensis, Lawsonia inermis, Murraya inermis and Murraya koenigii displayed MFC values
koenigii of 0.2 mg/mL (ZOI = 11-13 mm). On the contrary,
Hibiscus rosa-sinensis exhibited lower fungicidal
activity (1 mg/mL) and the lowest ZOI (2 mm)
H. perforatum roots total methanolic ex- The MeOH extract, richer in xanthones, was the most [91]
tracts and fractions active against M. furfur (MIC90 = 32 µg/mL). The
prepared with CHCl3, inhibition % of biofilm formation, at concentration of
EtOAc and MeOH 16 µg/mL, ranged from 14% to 39%; the best results
were obtained with the CHCl3 fraction.
Essential oils of T. kotschyanus, Z. mul- water Z. multiflora essential oil (rich in carvacrol) showed [92]
tiflora, R. officinalis, A. sieberi, M. spi- MIC90 values ranging from 30 to 80 mg/mL. M. nana
cata, and H. persicum isolates were the most susceptible (30 mg/mL),
whereas M. slooffiae isolates were shown to be the
least sensible to the treatment (80 mg/mL). Itracona-
zole (MIC90: 2.8 mg/mL), amphotericin B (MIC90: 3
mg/mL) and fluconazole (MIC90: 7.8 mg/mL) were
used as standard inhibitors
Tea tree oil water A large number of M. furfur isolates were assayed [93]
providing MIC50 and MIC90 values of 0.25%.
C. aggregata lichen ethanol MIC (mg/mL) values of 2.72, 0.63, and 1.28 against [94]
M. furfur, M. globosa and M. sympodialis, respec-
tively, while no activity was recorded against M. re-
stricta. Fluconazole was used as the reference stan-
dard (MIC values ranging from 0.006 to 0.051
mg/mL)
Nyctanthes arbor-tristis L. leaves ethanol MIC values of the ethanolic extract for M. globosa [16]
7966, M. furfur 1878, M. restricta 7877, and M.
sympodialis 9974 ranged from 1.05 to 1.47 mg/mL
(MFC= 3.12 mg/mL) and its effect influenced cell
membrane integrity
Aloe barbadensis, Hibiscus rosa sinen- distilled water ZOIs (cm) were evaluated by cup plate method. Cit- [95]
sis, Lawsonia inermis, Snake guard, rus limonis and Emblica officinalis fruits dis-
Wrightia tinctoria, Eucalyptus globulus, played the best inhibitory activity (also in associa-
Azadirachta indica, Allium sativum, tion)
Allium cepa, Citrus limonis, Sapindus
mukorossi, Trigonella foenum graecum,
Emblica officinalis, Acacia concinna
Grape (Vitis vinifera L.) seeds ethanol/water (7:3 The inhibitory activity has been correlated with the [96]
v/v) acidified with content of monomeric and polymeric flavan-3-ols
formic acid at pH 3 (MIC50= 32 µg/mL)
Malacalm (Citrus aurantium 1%, commercial product MIC value for Malacalm was lower than single es- [97]
Lavandula officinalis 1%, Origanum of a mixture of essen- sential oils. The most abundant components were
vulgare 0.5%, Origanum majorana tial oils in sweet al- also tested in vitro against M. pachydermatis be-
0.5%, Mentha piperita 0.5%, Helichry- mond oil and coconut ing thymol and carvacrol the most promising anti-
sum italicum var. italicum 0.5%) oil fungal agents. In vivo tests were also performed
2404 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

OH
O O OH
O
HO
H H O OH OH
OH
H H HO
HO

ß-Sitosterol Calceolarioside A

Fig. (11). Natural compounds able to interact with Mala s 1.

A large number of plant extracts (Eucalyptus globu- aqueous silver ions into AgNPs and antifungal activity
lus, Aloe vera, Zingiber officinale, Wrightia tinctoria, against M. furfur [101] AgNPs synthesized from M.
Cassia alata, Azadirachta indica, Phyllanthus emblica) phaseolina showed the maximum antifungal activity
were tested for their inhibitory activity against M. fur- against M. furfur (24 mm of ZOI). AgNPs were also
fur (see previous paragraph). In cosmetic formulations synthesised using flavonoids-enriched Coriandrum sa-
there is a preference for natural surfactant (saponin)- tivum leaf extract [102] and their in vitro anti-dandruff
based shampoos. Recent studies proposed natural efficacy against Malassezia furfur MTCC 1374 was
saponins from Sapindus mukorossi, Vernonia cinerea, assessed (MIC of 25 µg/mL).
Asparagus racemosus, Ricinus communis and Acacia
concinna as promising antimicrobial, antioxidant and 2.7. Mono and Diacylglycerol Lipases of M. globosa:
LIP1 (SMG1) Inhibitors
antidandruff agents. The synthesis of AgNPs was ob-
tained using the Aegle marmelos or Acacia auriculi- Starting from the available crystal structure of
formis aqueous extract [99]. The addition of AgNPs SMG1 (PDB: 3UUE) [103], a virtual screening on a
hampered the resistance of M. furfur 1374 to the treat- total of 170,000 compounds, docked into the substrate
ment and limited the final dose suitable for the antifun- binding pocket, was performed selecting 147 commer-
gal efficacy. The zone of inhibition (ZOI) towards M. cially available compounds for experimental testing on
furfur increased following the reduction of nanoparticle SMG1 Lipase assay using different substrates and RHC
size. In addition the cell shape and surface were sig- 80267, a well established inhibitor of mammalian dia-
nificantly altered after the treatment with AgNPs. cylglycerol lipases, as a reference drug [19]. Values are
reported in Table 4 as IC50, a measure of the effective-
Antifungal activity of spherical- and rod-shaped
ness of these substances in inhibiting this enzyme. IC50
AgNPs was investigated against M. furfur [100]. is defined as the drug concentration required for 50%
AgNPs and known antifungal drugs such as ketocona- inhibition in vitro.
zole and itraconazole, as reference drugs, were chal-
lenged by agar diffusion method. It was determined Comparing these biological data to molecular mod-
that 20 nm NPs induced ZOI values higher than 50 nm elling studies, it emerged the higher inhibitory activity
spherical NPs. 20 nm spherical-shaped AgNPs at 0.5 of 1 (seven-membered ring, IC50 = 20.09 µM) and 4
mg/mL exhibited antifungal activity higher than 50 nm (five-membered ring, IC50 = 22.86 µM) with respect to
rod-shaped AgNPs. Smaller AgNPs were more promis- the reference drug (IC50 = 75.25 µM). Compound 1 was
ing for antifungal drug development owing to a deeper shown to establish H-bonds with Leu172 and Thr101
cell wall rupture, a reduced cellular respiration and cell (pivotal residues also for RHC 80267), as well as hy-
drophobic interactions with two different pockets in the
death. The MICs were 0.2 mg/mL for 20 nm and 50 nm
active site, thus orienting the sulfur atom towards
AgNPs and 0.3 mg/mL of rod-shaped nanoparticles.
His281 and Gln282. These residues are strongly con-
Successively, in vivo antimicrobial effect and tolerabil-
served in many lipases within Family Lipase 3 secreted
ity of AgNPs on rat’s skin surface were evaluated. On
by M. globosa. The binding affinity was unfavourable
continued application of AgNPs, regression in redness
both when oxygen atom is added to the cyclic lateral
was visible upon skin permeation. No pathological
substituent (six-membered ring, 8) and a further car-
signs were found in any sacrificed animal. The activi-
bonyl function was present in the oxo-isoindoline nu-
ties of specific antioxidant enzymes were also pre- cleus (5-7), limiting the number of molecular interac-
served. tions within the enzyme. The other compounds, 2 and
F. oxysporum, F. oxysporum f. sp. vasinfectum and 3, are less active (IC50 of 81.75 µM and 98.34 µM, re-
M. phaseolina also showed the ability to reduce the spectively).
Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2405

Table 4. Experimentally determined IC50 of the reported SMG1 inhibitors.

IC50 µM
Compound Structure
(Substrate)

O 20.09 ± 7.00
(pNPA)
N 0.19 ± 0.06
1 S (monoolein)
N 24.36 ± 4.64
S (pNPC)

O
81.75 ± 20.69
2 HO O (pNPA)

HO

N S 98.34 ± 19.21
3 O (pNPA)

N 22.86 ± 4.92
4
S (pNPA)
N
S
O

N 63.60 ± 10.31
5
S (pNPA)
O N
S

N >200
6 S (pNPA)
O N
S

N >200
7
S (pNPA)
O N O
S
O

N >200
8
S (pNPA)
N O
S

O
H
N N O 75.25 ± 10.30
RHC 80267 O N N (pNPA)
H
O

IC50s are expressed as mean ± SE using pNPA (p-nitrophenol acetate), monoolein and pNPC (p-nitrophenol octanoate) as substrates.
2406 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

OH

N
O
O
N N F

1 2

N
R N
O O
O

3 4

NH N
O O O
O O

5 6

Fig. (12). Fenpropimorph derivatives.

To corroborate the biological activity of compound and their cytotoxicity. Moreover, this compound pro-
1, an additional lipase assay using monoolein, was car- tects from pathogens, decreasing their virulence and
ried out, showing a concentration-dependent inhibition enhancing their susceptibility to antimicrobial agents
with lower IC50. It is also important to highlight that [105].
IC50 values of compound 1 did not change using other
substrates (from 6.7 mM with pNPA to 41.7 µM with HS
O
H
pNPC). Moreover, according to the Lineweaver-Burk HOOC N COOH
N
plots, this inhibitor acted in a competitive fashion, as H
NH2 O
well as RHC 80267.
Fig. (13). Structure of glutathione.
2.8. Fenpropimorph Derivatives
Fenpropimorph derivatives (1-6, Fig. 12) were cho- This natural agent did not infer any inhibitory activ-
sen not only as inhibitors of the growth of one strain of ity against GSH-treated M. furfur cultures ranging from
M. furfur (CCY 85-2-1) and two strains of M. pachy- 200 to 1000 µg/mL, when compared with untreated
dermatis (CCY 85-1-5, CCY 85-1-10) in comparison cultures, but it was shown to:
with bifonazol, but also for their ability to change the 1. inhibit cell surface hydrophobicity (CSH) at 400
composition of the fungal membrane fatty acids, rather µg/mL (from 84% to 95% in four Malassezia spp.).
than their effects on ergosterol. The minimum inhibi- CSH is a pivotal virulence factor contributing to
tory concentrations were determined by the microdilu- form biofilm, to reduce phagocytosis of pathogens,
tion method [104]. and to enhance the release of inflammatory cytoki-
Compounds 1 and 2 were weak inhibitors for all nes. CSH also strictly depends on the huge amount
tested strains, whereas 3 and 4 were only medium ef- of lipids in Malassezia cell wall;
fective against two isolates of M. pachydermatis. Fi- 2. delay cell aggregation reducing CSH value without
nally, compounds 5 and 6 strongly reduced the growth interfering with the cell surface charge, as demon-
of Malassezia. Moreover, the presence of compound 5 strated by the anti-hydrophobicity activity (AHA) of
induced adaptive changes not only in the sterols pro- GSH and through FT-IR analysis;
file, but also in fatty acids content and composition. 3. modulate cell surface charge (CSC) in M. furfur as
extrapolated by Zeta Potential measurements;
2.9. Glutathione
4. reduce Hydrophobicity Index (HI) at 400 µg/mL by
Glutathione (GSH, Fig. 13) is a sulfur-containing evaluation of the minimal hydrophobicity inhibitory
tripeptide, which neutralizes reactive oxygen species concentration (MHIC) value.
Natural/Synthetic Anti-Dandruff Agents Current Medicinal Chemistry, 2017, Vol. 24, No. 22 2407

NH2 OH NH2

N N+ N N+ N N+
S OH S OH
N N N

Thiamine Oxythiamine Amprolium

NH2 OH
OH
N N N N N N
S OH S OH
N N S N N

Thiochrome Tetrahydrothiamine Tetrahydrooxythiamine

Fig. (14). Thiamine and its derivatives tested against Malassezia.

HO Cl

H 3CO H 3CO
O O

O OH O OH
N N
O O
O O O O
OH OH
O O

OCH3 OCH3
OCH3 OCH3

Tacrolimus Pimecrolimus

Fig. (15). Calcineurin phosphatase inhibitors.

2.10. Thiamine Derivatives phatase inhibitors hampering both TH1 and TH2 cyto-
kines release following T-cell activation and prolifera-
Taking into advantage of the cell growth inhibition
tion.
in S. cerevisiae by thiamine analogs (Fig. 14) responsi-
ble of impairment of important thiamine diphosphate- The former was tested against a large number of
dependent enzymes activity, the Krebs cycle and pen- strains belonging to different Malassezia spp. (MICs
tophosphate pathway, a recent research investigated ranging from 16 to 64 µg/mL) [41]. The latter also con-
their antifungal effect against M. pachydermatis [106]. trasted the in vitro growth of Malassezia spp. (MICs
from 16 to 32 µg/mL) [107]. The rationale of this ap-
Only oxythiamine was the most promising as re-
proach took advantage of the following evidence:
gards the growth inhibition at 40 µg/mL, probably due
to its specific intracellular phosphorylation by pyro- • a calcineurin homologue has been reported in fungi
phosphokinase and its incorporation in thiamine- and tacrolimus also exerted a toxic effect against C.
containing enzymes. Oxythiamine assimilation also neoformans and C. albicans [108];
causes pyruvate accumulation, inhibition of malate de- • from synergism test, when itraconazole and keto-
hydrogenase, Krebs and glyoxalate cycles reducing conazole were added to tacrolimus, their corre-
energetic production and, eventually, the total fatty ac- sponding MIC values were lowered. The FICI, cal-
ids content of the cell wall of M. pachydermatis. culated dividing the MIC of the combination of
compound and the antifungal reference drug by the
2.11. Pimecrolimus and Tacrolimus as Calcineurin
MIC of compound or antifungal reference drug
Phosphatase Inhibitors
alone, and interpreted as indicating a synergistic ef-
Pimecrolimus and tacrolimus (Fig. 15), two asco- fect when it was ≤0.5, as additive or indifferent
mycin macrolactam derivatives, are calcineurin phos- when it was >0.5 and ≤2, and as antagonistic when
2408 Current Medicinal Chemistry, 2017, Vol. 24, No. 22 Angiolella et al.

it was >2) [109, 110] was below 0.5 (synergistic ef- phosphatase inhibitors should also be another innova-
fect) against M. globosa, M. restricta, M. furfur and tive field of research, but up to date few inhibitors were
M. sympodialis. designed and tested to validate this approach. Other
• the comparative efficacy of topical administration of compounds were scarcely characterized in terms of
tacrolimus with respect to clotrimazole has been antifungal activity (MIC, MFC, FICI), cytotoxicity
also assessed in a single blind, randomized clinical against human cell lines, target selectivity and pharma-
trial for the treatment of pityriasis versicolor [111]. cokinetics. However, the possibility of combining two
drugs usually gave the best results as demonstrated for
CONCLUSION AgNPs encapsulating azole drugs or natural products.
In addition, these nanomaterials could be efficiently
Due to the emerging number of Malassezia spp.- compatible with several cosmetic formulations (HJ
related infections over the last few decades, it is man- shampoos, lotions and conditioners).
datory for the medicinal chemists to provide new and
innovative tools to eradicate this lipophilic yeast or re- CONSENT FOR PUBLICATION
duce its uncontrolled growth in predisposing condi-
tions. The limited arsenal currently available for this Not applicable.
treatment, which is mainly composed by old azole
CONFLICT OF INTEREST
drugs, could not stem recurrence and cross-resistance.
For this reason, we have collected novel and very re- The authors declare no conflict of interest, financial
cent approaches designing MgCA inhibitors, lipase or otherwise.
inhibitors, AgNPs combined with natural products, cal-
cineurin phosphatase inhibitors and other compounds ACKNOWLEDGEMENTS
for the treatment of Malassezia spp. Declared none.
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