2. human cells [15]. Accordingly, the development of selective antifungal
drugs with lower side-effect is a hotbed of research among medicinal
chemists [16].
1.2. Current medications
Currently, there are several well-known mechanisms to treat sys
temic and superficial fungal infections using roughly 40 branded anti
fungal drugs in the market and the other drug candidates in clinical
trials, which adopt new or convenient mechanisms to target fungi
(Fig. 1) [2,17–20].
Interestingly, the previous studies have introduced some new tar
gets to combat fungal infections, hoping that the emerging strategies
may yield the treatment for resistant fungal infections (Fig. 2) [21–24].
Despite new research and development in this field, there is still no
new approved drug for the more recent strategies. As shown in Figs. 1-
14-α demethylase inhibitors (azoles) are the most important and the
most approved clinical candidate drugs.
According to previous studies, classified azoles cover several char
acteristics of the most potent antifungals. Over the past half-century,
this family has had a significant effect on controlling invasive and su
perficial fungal infections. Their newer generation further increased
highly desired properties such as safety, lower risk of drug-drug inter
actions, proper pharmacokinetics, and improved activity spectrum
[25–27].
With the large number of azole antifungals in the clinics and in
experimental medicinal chemistry institutions, keeping track of pro
mising molecules that are under development is challenging for the
researchers in the field. In this paper, we provide a comprehensive
review and an update of all approved and clinical candidates of azole
antifungal drugs, as azole pedigree in regard to their structural simi
larities. Herein, the description of the target, salient medicinal chem
istry points regarding azole structures (SAR), and the selectivity of these
structures for the concerned target are discussed. Furthermore, hybrid
antifungal agents as a prospective future generation are introduced to
pave the way for developing new efficient azole antifungal structures in
the future.
2. Azole family
2.1. History and pedigree
The first report on the antifungal activity of an azole compound was
presented by Woolley (1944), a serendipitous discovery that declared
the antimycotic effect of benzimidazole moiety for the first time [28].
Afterwards, several other researchers indicated other azole antifungal
structures such phenethylimidazole [29] and substituted benzimida
zoles [30]; however, none of these reports led to the development a
drug until 1958, when chlormidazole (1, Fig. 3) was introduced, the
first azole drug marketed by Chemie Grünenthal. Accordingly, chlor
midazole was the pioneer of enormous research on azole antifungal
activities. Currently, there are about 40 azole-containing drugs and
drug candidates, which could be classified into more than three gen
erations [15,31,32]. This field of study is still of great interest.
2.1.1. First generation
The first generation of azole family emerged with the introduction
of three compounds: clotrimazole (13) from Bayer AG in 1969,
Janssen’s miconazole (2) at the same time, and later econazole (3) in
1974. These three drugs were launched as topical antifungal agents
making azoles an indispensable asset in treating fungal infections[15].
Following the discovery of these early structures, several analog com
pounds are marketed, which can be categorized into the first-generation
group due to their similar physiochemical properties and indications in
treating superficial fungal infections such as dermatomycoses, tinea
versicolor, cutaneous, and vaginal candidiasis as well as topical for
mulations. Considering their structures, they have similar imidazole-
contained backbone and could be further sub-divided into three cate
gories: miconazole-based structures, clotrimazole- based structures, and
vinyl-imidazole derivations, as shown in Fig. 4.
Fig. 1. Antifungal drugs. the number of approved and clinical trial agents are summarized.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
2
3. Miconazole (2) has well-documented activity in the treatment of
oropharyngeal candidiasis as well as vulvovaginal candidiasis, tinea
corporis, tinea pedis, and tinea cruris [33]. It also has a fungicidal ac
tivity via direct membrane damage. Clinically, miconazole adminis
tration routes are topically or intravenously; however, miconazole in
fusion is also associated with adverse reactions such as nausea, fever,
and more importantly cardiotoxicity when rapidly infusing that was
due to a formulation containing Cremophor® EL because of its low so
lubility [34]. All the miconazole analogs are derived from a key inter
mediate, 2-(imidazolyl)-acetophenone. The only exception is butoco
nazole (11), which is derived from 4-(4-chlorophenyl)-1-(1H-imidazole-
1-yl) butan-2-ol structure.
According to FDA, clotrimazole (13) is safe and effective for the
prevention and treatment of oropharyngeal, vulvovaginal, and
cutaneous candidiasis and the other superficial dermatologic infections
[35].
Clotrimazole (13) synthesis was reported three years after its de
velopment. Benzophenone derivations could be used for clotrimazole
(13) and bifonazole (14), and dibenzosuberone for eberconazole (15)
synthesis. Becliconazole (16) is a new clotrimazole-like compound,
which is recently entered into the clinical trials from Menarini
Company.
Luliconazole (21), the newest first-generation azole approved by
FDA, contains a unique vinyl-imidazole structure. It has a broad-spec
trum topical effect against dermatophytes such as Trichophyton rubrum,
Microsporum gypseum and Epidermophyt on floccosum [36]. In this group,
TS-80 (22) entered into phase-I clinical trial from Shikoku company and
revealed an activity against cutaneous fungal infections; however, this
trial has not yet been completed.
2.1.2. Second generation
For second generation azole antifungals, there are three main
changes in the structure of the compounds which resulted in many
improvements in terms of the safety, spectrum of action, and pharma
cokinetics of azole drugs. It should be noted that following the second
generation of azoles, subsequent generations are just modifications and
analogs of these structures.
In this regard, the main changes are evident in Janssen's (1981)
antifungal ketoconazole (23), the first drug containing a heterocyclic
dioxolane functional group, replacing the ketone with a new long-tail
Fig. 2. New fungal cell targets.
(1)
Fig. 3. Structure of chlormidazole (1).
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
3
4. structure; however, the imidazole moiety remained similar to its pre
decessor. This was the first orally active, broad-spectrum azole to treat
systemic mycoses [37].
Although ketoconazole (23) has several drawbacks resulting in a
black box warning from the US FDA, it was preferred to amphotericin B
(AmB) for non-life threatening systemic fungal infections until 1990
[38]. One of the major problems with ketoconazole (23) is hepato
toxicity caused by CYP450 inhibitions, indicating the imidazole-con
tained lower selectivity for fungal compared to mammalian P450 en
zymes. The other prevailing problems are bioavailability and
pharmacokinetic interactions, which finally led to removal of this drug
from the FDA list of approved medication to treat systemic mycosis in
2013 [39].
The third and the most important breakthrough in the development
of azole structure was the introduction of a triazole ring replacing the
bygone imidazole moiety in the azole structures. Triazole was first used
along with fluconazole (24) developed by Pfizer (1989) [40]. The su
perior advantages of fluconazole (24) were selectivity for fungal CYP
enzyme over mammalian, a larger spectrum of action, increased
metabolic stability, lower protein binding, enhanced bioavailability,
greater water solubility to be used as intravenous indications, high CNS
penetration, and lower side-effects [41–43]. Interestingly to achieve
higher IV bolus administration of fluconazole (24) in clinics, even
greater solubility was necessary. This problem was solved using a
phosphate ester of fluconazole (24) which was approved in 2003 [44].
Fosfluconazole (28) could be active with the action of alkaline phos
phatase enzymes [45].
The discovery of fluconazole (24) is one of the most interesting
medicinal chemistry studies on the modification of a structure to
achieve desirable properties (Fig. 5) [46]. In its synthesis, an epoxide
ring (Fig. 6A) is the key intermediate achieved by well-known Corey-
chaykovsky epoxidation with trimethyl sulfoxonium iodide (TMSI) re
agent employed as the ring closer [47–50].
At the same period, another important triazole-based structures
improved by Janssen pharmaceuticals were terconazole (25) and itra
conazole (26) [15], both of which had a long-tail structure to similar
that of ketoconazole (23) as well as similar low bioavailability. They
have several side-effects, including cardiotoxicity. Although they have a
Fig. 4. First generation azole structures: A: miconazole (2) analogs, B: clotrimazole (13) analogs, C: Vinyl-imidazole structures.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
4
5. broader spectrum of antifungal activity in comparison to ketoconazole
(23) and fluconazole (24), they couldn’t be an alternative to fluconazole
(24) in many cases [51–53]. Itraconazole (26), however, was preferred
to ketoconazole (23) in the treatment of mycoses, Blastomycosis and
invasive aspergillosis [54,55]. In terms of synthesis, itraconazole (26)
and similar structures utilize a common route through dioxolane in
termediate formation at four major steps (Fig. 6B) to form the targeted
compound [37].(See Table 1)
When the first-generation structures were compared to the second-
generation (Fig. 7), the latter generation improved upon the spectrum
of activity and added routes of administration; however, there were still
challenges regarding pharmacokinetic and safety profiles. Conse
quently, the third generation of azole drugs were the improved struc
tures of the second generation and could be sub-divided into two groups
of fluconazole (24) and itraconazole (26)-like structures. Table 2 shows
the major physiochemical and pharmacokinetic properties of the main
second-generation azole drugs [45,56,57].
2.1.3. Third generation
With the increasing concerns about the high incidence of fungal
infections, new structures emerged as the third-generation azoles or
triazole generation. These drugs are improved structures of the second-
generation antifungals divided into two groups of fluconazole (24) and
itraconazole (26) like structures (Fig. 8). In both of these groups of the
third generation, major medicinal chemical efforts were made to im
prove pharmacokinetic properties and safety profile, extend the spec
trum of activity, and, more importantly, design a structure to combat
resistant types of fungal infections. In Table 3, major physiochemical
Fig. 4. (continued)
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
5
6. and pharmacokinetic properties of several third generation drugs are
listed [58–67].
Since fluconazole (24) is inactive against molds such as Aspergillus
spp and increases the resistance of Candida spp, in 2002, the FDA ap
proved voriconazole (30) produced by Pfizer with a fluoropyrimidine
ring instead of the second triazole of fluconazole (24) [68]. This
structural difference has made the compound > 30 fold more potent for
C. albicans, 20 fold more potent for C. glabrata, and completely active
against all Aspergillus spp [69].
In 2004, the Schering Plough Research Institute working on a new
lead, SCH51048, observed that antifungal activity was higher than the
hypothesized concentration, suggesting the presence of an active
metabolite. Following LC-MS/MS analysis, a hydroxylated metabolite
was discovered. By using this as a lead and after synthesis of all side-
chain monohydroxylated diastereomers, posaconazole (31, SCH56592)
was discovered as a new triazole antifungal agent, providing a prime
example of active metabolite-based drug design (Fig. 9) [70,71].
Posaconazole (31) showed a broader spectrum of activity against all
fungus organisms covered by other new broad-spectrum antifungal
drugs. Moreover, it had an additional activity against Zygomycetes,
Scedosporium spp, and also was effective in the treatment of CNS fungal
infections and cryptococcal meningitis [72].
The FDA approved posaconazole (31) for prophylaxis of invasive
Aspergillus or Candida infections in hematopoietic stem cell
Fig. 4. (continued)
Fig. 5. Fluconazole (24) structure optimizations.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
6
7. transplantation (HSCT) recipients with graft versus host disease
(GVHD), as well as in patients with hematologic malignancy with
prolonged neutropenia and oropharyngeal candidiasis [73–75].
Efinaconazole (32), as a new topical triazole antifungal for the
treatment of mild to moderate onychomycosis, received its first global
approval on October 3, 2013 in Canada by Valeant Pharmaceuticals
International. This compound has a better safety profile compared with
the oral treatment of onychomycosis [76].
In cases of intravenous formulations of posaconazole (31), vor
iconazole (30), and itraconazole (26), cyclodextrin is added to increase
solubility, which is of concern due to potential nephrotoxicity [77].
This concern was remedied by the medicinal chemistry work of Basilea
Pharmaceuticals and Astellas Pharma. Isavuconazonuim sulfate, a
water-soluble prodrug of isavuconazole (33) containing a 1-[N-methyl-
N-[3-[2-(methylamino)acetoxymethyl]pyridyn-2-yl]amino carbony
loxy] ethyl substituent, easily converts to its active form by the action of
plasma esterase (Fig. 10). Therefore, the oral and intravenous for
mulation no longer needs cyclodextrin for enhanced solubility [78,79].
(See Fig. 11)
As a broad-spectrum azole drug, isavuconazole (33) has an anti
fungal activity profile similar to that of voriconazole (30). In 2014, the
FDA approved it for treatment of invasive aspergillosis [80].
Another example of triazole antifungal in clinical trials is ravuco
nazole (34), with a slight difference in structure compared to
isavuconazole (33), but with a similar antifungal profile to that of
voriconazole (30). Ravuconazole (34) is active against fluconazole (24)
and itraconazole (26) resistance infections. It was discontinued from
phase II for aspergilusis and candidiasis in August 2007, and was re
placed with fosravuconazole bis(L-lysine) created by Bristol-Myers
Squibb. The first global approval of this prodrug of ravuconazole (34)
with the brand name of NAILIN® as 100 mg capsules was for onycho
mycosis in Japan on July 27, 2018 [81].
Albaconazole (35) with a 7-chloro-quinazoline-4-one structure
bears more potent antifungal in vitro activity than Amphotericin B.
Furthermore, a wide spectrum of action and favorable pharmacokinetic
with safety profile [82] was originated by Grupo Uriach. In 2013, Al
lergan (Actavis Inc) picked up the worldwide rights for albaconazole
(35) from Palau Pharma S.A.
Other new compounds of this generation are also currently in phase-
III, such as genaconazole (36) and iodiconazole (37), phase II such as
saperconazole (39), ICI-D0870 (42) and UR-9751 (41), and phase I such
as embeconazole (38), DUP-860 (40), SS-750 (44), SSY-726 (46) and
PC-945 (47). Moreover, some new structures like UR-9660 (43) and
SDZ-89–485 (45) are in preclinical stages [18–20,83].
Many triazole alcohol derivations have been investigated and sev
eral new and known scaffolds incorporated into their structures are
assessed in terms of their antifungal activity [84–86]. This new tech
nique for antifungal agent discovery is highly growing in medicinal
Fig. 6. Second generation azole drugs intermediates synthesis, A: The intermediate of Iitraconazole (dioxalene) synthesis roots. B: Fluconazole’s intermediate
(epoxide) synthesis root.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
7
8. chemistry research [87–95].
2.1.4. Fourth generation
In the previous generations, new structures successfully emerged
and solved the resistance, potency, the spectrum of action, and phar
macokinetics problems of azole family. One of the main problems,
known as the ‘Achilles heel’ for azoles, is the drug-drug interactions
caused by probable human CYP3A4 enzyme inhibition [33]. This pro
blem is a concern since many patients suffer from complicated
conditions such as AIDS, cancer, and impaired immune function and
need polypharmacy. The metal binding region in azole structures is the
main part of the inhibitory effect as for human CYP3A4 inhibition.
Following the replacement of imidazole with triazole ring, the se
lectivity increases, even though, the problem still exists. Successful ef
forts have been made in Viamet Pharmaceuticals, Inc. (Durham, NC,
USA). Using an appropriate medicinal chemistry strategy, they in
troduced three novel azole structures (Fig. 10) with high selectivity for
fungal CYP51 and increased potency and desirable pharmacokinetics
and physiochemical properties (Table. 4), in comparison to the other
structures [96–98]. Replacement of high-avid metal binding and more
potent triazole ring with less-avid metal binding and less potent tetra
zole ring and the compensation of low potency with modification of
side-chain were performed to have the more selective and potent
fourth-generation of azole structures [99,100].
They used voriconazole (30) for its lower anti-target (CYP3A4) af
finity compare to the other azoles, as a leading compound to design new
compounds. Quilseconazole (48, VT-1129) is now in phase I clinical
trial in cryptococcal meningitis. It has had a promising efficacy in the
murine model and increased one-month survival, compared to fluco
nazole (24). In Jun 2016, VT-1129 (48) received Fast Track orphan
drug designation for the treatment of cryptococcal meningitis [PO] (in
volunteers) in the USA [101,102].
Table 1
First generation azole information’s about important physiochemical proper
ties.
Generic name Physiochemical properties
CLogP1
tPSA2
LogS3
Becliconazole 4.83 24.83 −5.94
Bifonazole 4.74 15.6 −6.28
Butoconazole 6.86 15.6 −7.56
Clotrimazole 5 15.6 −6.97
Croconazole 4.5 24.83 −5.68
Dapaconazole 5.26 24.83 −6.64
Eberconazole 4.97 15.6 −6.1
Econazole 5.1 24.83 −6.39
Fenticonazole 6.72 24.83 −8.23
Flutrimazole 4.57 15.6 −6.75
Isoconazole 5.8 24.83 −7.08
Luliconazole 3.49 39.39 −5.54
Miconazole 5.8 24.83 −7.09
Neticonazole 4.24 24.83 −5.48
Omoconazole 6.06 34.06 −7.44
Oxiconazole 6.46 37.19 −7.69
Sertaconazole 6.16 24.83 −7.45
Sulconazole 6.27 15.6 −7.02
Tioconazole 4.78 24.83 −5.76
Ts-80 5.52 32.6 −6.98
Zinoconazole 5.08 39.9 −6.198
1. Calculated octanol–water partition coefficient, 2. Topological polar surface
area, 3. Aqueous solubility
Fig. 7. Second generation azole drugs structures.
Table 2
Major physiochemical and pharmacokinetic properties of important second
generation azole drugs.
Generic name Physiochemical properties Pharmacokinetic properties
CLogP1
tPSA2
LogS3
PPB (%)a
Half-life
(h)
Vd (L/
Kg)b
Fluconazole −0.44 76.15 −2.127 12 31 0.7
Itraconazole 5.98 98.04 −9.752 > 95 64 11
Ketoconazole 3.63 66.84 −6.421 > 95 8 No data
1. Calculated octanol–water partition coefficient, 2. Topological polar surface
area, 3. Aqueous solubility a: plasma protein binding, b: volume of distribution
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
8
9. Oteseconazole (49, VT-1161) another tetrazole compound after
successful phase III trial for vulvovaginal candidiasis in March 2019
(PO, Capsule) (NCT03840616), the Mycovia Pharmaceuticals and
Jiangsu Hengrui Medicine have teamed up to develop and market the
first FDA approved drug for vulvovaginal candidiasis [103,104]. VT-
1598 (50), with the broadest spectrum of antifungal activity among
tetrazoles, is the most recent compound from the tetrazole group [105],
whose important anti-coccidioidomycosis effect (in vitro MIC:
0.06–0.5 mg/L) import this compound to preclinical development in
USA (PO) [106]. Another multidrug resistance fungal spices, Candida
auris, is also affected by VT-1598 (50) with MIC of 0.03–8 mg/L in vitro
[107].
Following the efforts of Viamet pharmaceuticals, the significance of
side-chain optimization in increasing the potency and metal-binding
Fig. 8. Third generation azole drug structures (blue structures derived from fluconazole and red structures derive from itraconazole). (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
9
10. group tetrazole in having better selectivity became obvious. This new
family and all other new structures in clinical trials showed that an old
mechanism could be a new hope.
2.1.5. Hybrid structures as future azole-generation
The hit to lead process and further development to achieve a drug
candidate is time and cost consuming [108]. Classical combinatorial
chemistry or modern virtual screening approaches have not yet brought
a breakthrough in the discovery of novel drug candidates [109]. In
order to obtain new antifungal drugs that are affordable and able to
avoid the emergence of resistant strains, hybrid drug discovery comes
to mind. Molecular hybrids of biologically active structures are now
gaining momentum worldwide and may be a key tool in the arsenal of
medicinal chemistry efforts for drug discovery [110]. Hybrid or dual-
acting molecules are defined as combination of two or more chemical
scaffolds that act at different targets to create more specific and
Fig. 8. (continued)
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
10
11. powerful drugs [111].
Fluconazole (24) as a favorable antifungal drug due to its worthy in
vivo efficacy and pharmacokinetic property, has been attracted for
hybrid drug discovery. Fluconazole analogues obtained by facile
replacing one triazole ring by other potential antifungal scaffolds di
rectly or by using suitable linkers [112]. This new way to design
structures makes fluconazole hybrids potential future generation of
azole antifungals.
The triazole nucleus especially 1,2,3-triazole ring has been utilized
as a linker in various antifungal drug hybridizations by means of click
reaction [113]. Several research groups introduced 1,2,3-triazole ring
in the side chain of azole structure to design hybrid structures and
survey antifungal effects [90,114–118](Fig. 15). This motif act not only
as a linker, but also interacts efficiently with active site of CYP51
providing in many cases improved physiochemical properties of struc
tures [119].
Recently medicinal chemists have made considerable efforts to de
sign potent hybrid antifungal structures of fluconazole, some of which
are summarized (Fig. 12).
Natural products are a dominant source of biologically active
structures and hybridization of these structures with fluconazole can
lead to potent drugs [108]. Zhang et al, [89] report design and synthesis
of novel series of carbazole-triazole conjugates. Carbazole derivations
as naturally occurring phytochemicals are known for pi-conjugated
Table 3
Major physiochemical and pharmacokinetic properties of several 3rd genera
tion azole drugs.
Generic name Physiochemical properties Pharmacokinetic properties
CLogP1
tPSA2
LogS3
PPB (%)a
Half-life (h) Vd
(L/
Kg)b
Voriconazole 0.52 72.91 −2.72 58 6 4.6
Posaconazole 4.1 109.04 −8.82 > 95 25–31 428
Efinaconazole 2.14 51.43 −2.97 – 29.9 –
Isavuconazole 2.68 84.34 −5.19 98 56–77 6.5
Ravuconazole 2.68 84.34 −5.2 98 76–202 10.8
Albaconazole 2.14 80.86 −4.72 98 30–56 Very
large
1. Calculated octanol–water partition coefficient, 2. Topological polar surface
area, 3. Aqueous solubility a: plasma protein binding, b: volume of distribution
Fig. 9. Active metabolite of early lead SCH51048, posaconazole (31, SCH 56592).
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
11
12. motifs that could inhibit topoisomerase, intercalate with DNA, and also
disrupt the integrity of the microorganism membrane [120]. Their ef
forts led to compound A (Fig. 12) with MIC = 2–32 µg/mL against most
of the tested fungal strains. Compound A also, intercalates into DNA to
possibly block DNA reproduction. Elias et al [121] in an effort for
synthesis new azole hybrids with coumarin and quinolone scaffold
showed that their coumarin hybrids antifungals (compound B, Fig. 12)
could penetrate into endoplasmic reticulum of fungal cells where, true
target CYP51 generally exist in. This potentially can enhance the effi
cacy of azole antifungal drugs.
Combination of known antifungal, antimicrobial, and anticancer
drugs to azole structures are also among high interest. This hybridiza
tion will help to combat resistance strains due to the possibly different
mechanism of actions. Experiments conducted by Sheng et al, [122]
elucidate design and synthesis of the first CYP51/HDAC dual inhibitors.
They successfully developed potent antifungals agents with activity
against azole-resistant clinical isolates. The HDAC family of proteins are
key enzymes involved in gene regulation, cell proliferation, and are
known anticancer targets. Vorinostat (SAHA) (Fig. 12) an HDAC in
hibitor, was previously confirmed to possess synergistic effects with
fluconazole (24) against azole-resistant strains. Inspired by these find
ings, new anti-fungal dual inhibitor hybrids emerged. Compound C,
with MIC = 0.25–0.5 µg/mL and potent in vivo efficacy against azole
resistance candidiasis was introduced as the best CYP51/HDAC hybrid.
Before this, they also designed a hybrid of rosiglitazone and other de
rivations of thiazolidinedione with fluconazole (Fig. 12) and
investigated anti-fungal activities. Their target compound D, with MIC
values against C. albicans in the range of 0.03–0.15 µM, proved the
efficiency of dual inhibitors in antifungal drug discovery [111].
Another team, studied the antifungal activity of 5-flucytosine
combination with fluconazole (123, Fig. 12). Two potent antifungals
combined in one molecule. Their efforts led to compound E with
MIC = 0.008 and 0.02 mM against C. albicans ATCC 90,023 and clinical
resistant strain C. albicans respectively. They also showed that new
hybrids could permeate membrane of C. albicans and also could inter
calate into calf thymus DNA helix and block DNA replication by making
a steady supramolecular complex [123].
2.2. Mechanism of inhibition
The recognition of a bottleneck for efficient antifungal drug dis
coveries based on the eukaryotic nature of fungi and its similarities with
the human is necessitous. Similar to most of the other drugs, the be
ginning of azole class was by chance, and none of the antifungal drugs
were discovered using rational target-based drug design strategy.
One of the main targets of small molecules effective in combating
fungal infection is cell membrane and the biosynthesis of ergosterol, a
derivative of mammalian cholesterol. Ergosterol has several functions
in fungi, the important of which is its role in cellular proliferation. To
this end, a planar a-face (no methyl group at C14) structure and a
double bond in C5-6 are required to have these structural character
istics. There are several important enzymes in the biosynthesis pathway
Fig. 10. Activation of Isavuconazonium sulfate prodrug to its active drug.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
12
13. [124], one of the predominant enzyme in required is CYP51 (Lanestrol-
14α-demethylase) (ERG-11) from cytochrome P450 family, which cat
alyzes an oxidative removal of lanosterol, 14-methyl group and leads to
a 14–15 double bond (Fig. 13) [125]. In the active site of CYP51, an
iron-containing porphyrin provides oxygen for this first oxygen-de
pendent reaction in the ergosterol biosynthesis. Recently, several pa
pers fully-described the mechanistic details of CYP51 action [126–129].
Furthermore, a recent study showed that CYP51 might be involved
in distinct process of eluding human immune system, a finding that will
likely grow with the increase with the growth of research. [130]. Thus,
accumulation of methylated sterols would cause a fungistatic effect in
yeast and fungicidal effect in molds in most of the azoles, except in high
doses, and voriconazole (30) and itraconazole (26) (they are considered
to have fungicidal inhibition). Pertaining to immunocompromised pa
tients, the eradication of the fungal infection is of essence and fungi
cidal effects in therapeutic doses are highly beneficial [53].
Thus, knowing the enzyme structure is crucial for efficient
inhibition of CYP51 and designing selective and potent inhibitors.
Elucidation of the CYP51 structural information was challenging before
obtaining a complex of CYP51 orthologue from prokaryote myco
bacterium tuberculosis (carrying about a 33–35% sequence homology to
that fungal) with fluconazole (24). The reason is that purification and
crystallization of a highly hydrophobic membrane-bound protein is
arduous.
Information from other CYP51 orthologues is not useful. For ex
ample, VFV, as a potent anti T. cruzei drug candidate, today, has a weak
inhibitory effect on fungal CYP51. Moreover, VNI, as another anti-
Chagas disease drug candidate with an important H-bond interaction of
its carboxamide group with the T. cruzei active site, does not form any
H-bond in fungal active site protein [131–133]. However, biochemistry
works and X-ray crystallographic studies have recently developed a
protein expressed in some organisms like Escherichia coli, S. cerevisiae,
C. albicans, and C. glabrata and also in other important species
[129,134].
Fig. 11. Fourth generation azole drugs structures derive from voriconazole.
Table 4
Major physiochemical and pharmacokinetic properties of 4th generation azole drugs.
Generic name Physiochemical properties Pharmacokinetic properties
CLogP1
tPSA2
LogS3
PPB (%)a
Half-life (h) Vd (L/Kg)b
Quilseconazole 4.99 82.14 −6.59 No data > 6 days No data
Oteseconazole 4.67 82.14 −6.64 No data > 48 1.4
VT-1598 5.73 105.93 −7.91 > 95 22 No data
1. Calculated octanol–water partition coefficient, 2. Topological polar surface area, 3. Aqueous solubility a: plasma protein binding, b: volume of distribution
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
13
14. From many studies of azole binding site interactions in the ligand-
binding pocket of CYP51 in different species reported by diverse
groups, several common interactions have emerged with conserved
amino acids in the active site. The most conserved domain is heme-
binding pocket, and also motifs that donate to set the heme into the
core structure and some other residues on the surface of the active site
[135]. Recent biochemistry studies declare that the ligand-binding
pocket (LBP) in different species such as S. cerevisiae, C. glabrata, and C.
albicans has similarities with the structural and chemical characteristics
of lanosterol demethylase protein [135]. Azole drugs inhibit the en
zyme reaction by non-competitive reversible interaction with the heme
and prevent accessing of protons to the active site. There are several
similar interactions with other residues. For example, structures have
shown that C. albicans CYP51 protein complex with posaconazole (31)
or oteseconazole (49) has similar binding interactions with 22 amino
acids, on which oteseconazole (49) has an important H-bond with the
His-377 from its trifluoroethoxyphenyl oxygen (Fig. 14). His377 is
highly conserved in different fungal pathogens and also is specific for
fungi and not humans. This shows the importance of H-bonding in the
fungal CYP51 active site complex with inhibitors for potent and selec
tive drug design. Key binding pocket interactions for fluconazole (24) in
LBP of S. cerevisiae and oteseconazole (49) in C. albicans CYP51 active
site are presented in Fig. 14 [130,134].
Despite these similarities in the CYP51 amino acid sequences and
Fig. 12. Some of important fluconazole hybrid antifungal agents.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
14
15. interactions of different inhibitors with them, allowing for development
of selective inhibitors with a wide spectrum of action in CYP51 human
pathogens, it is necessary to study the conformation and binding in
teractions of each new inhibitor. This will permit and allow investiga
tion of target-driven information in the context of target-based drug
discovery, setting new interactions on selective and non-conserved re
sidues to reduce the risk of resistance in future [136,137].
Significant progress has been made with regard to information on
these X-ray crystal structures in characterization of CYP51 for anti
fungal drug discovery. Several complex structures of CYP51 with in
hibitors are available from RCSB Protein Data Bank (PDB) (rcsb.org).
The information on CYP51 structures is presented in Table 5
[127,134,136,138–142].
2.2.1. Structure activity relationship (SAR)
After the voriconazole (30) discovery, there were > 1000 flucona
zole-derived structures that were synthesized and experimentally tested
at Pfizer, an inefficient and costly process [143]. Therefore, to design
and survey new azoles, as a leading class of important antifungal drugs,
a good model of structure–activity relationships could be cost and time
beneficial. From many studies on azole structure–activity relationships
and others surveying interactions in target protein with x-ray crystal
lography or efficient docking methods, several useful pieces of in
formation have been obtained. Here, we gathered, modeled and sum
marized important structural features for future studies in the field.
In general, all azole drugs have a similar structural model (Fig. 15),
consisting of a Heme binding group, a three-atom linker, side-chain A
and side-chain B that are fully described below.
- Heme binding group:
This ring is crucial for the antifungal activity of the azole group
without any substitutions that bind to the linker with N-1 atom. The
basic N-3 of the imidazole ring or N-4 of the triazole or tetrazole ring is
positioned vertically to the porphyrin plane, as the iron of the active
site with the length of the coordinated bond of 1.2–2.1 A⁰. The basicity
of heteroaromatic nitrogen-containing rings does not have any re
levance with the inhibitory potency of the azole structure; however, it is
directly associated with liver toxicity and drug-drug interactions. We
can also define basicity as iron-binding affinity. Thus, tetrazole with the
lowest basicity (-1.1 vs 2.3 for triazole and 6.8 for imidazole) has
minimum inhibitory for CYP450 and related adverse effects
[99,128,144].
- The three-atoms linker:
Although we named this linker as a three-atom linker, it could be
varied between 1 and 4 atoms. This three-atom shape makes a special
distance between different arms of structure, leading to greater potency
[145]. The atom number 1 of the linker group in azole structures is
commonly carbon and does not have any substitutions except topical
agents such as clotrimazole analogs and vinyl imidazole derivations.
For the atom number 2 and 3 in the linker, which are mostly a carbon,
chirality is important for antifungal activity [146,147]. Presence of an
oxygen atom as a hydroxyl group on C-2 has several beneficial effects
such as enhanced potency due to an indirect H-bond via water mole
cules with active site, improved pharmacokinetics properties and water
Fig. 13. A. Sterol biosynthesis from Acetyl-CoA to ergosterol in fungi. B. The active site of CYP51[PDB: 4LXJ]: lanosrterol (green), heme (cyan), iron (orange),
oxygen(red) and Reaction steps catalyzed by C14-demethylase. (For interpretation of the references to colour in this figure legend, the reader is referred to the web
version of this article.)
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
15
16. solubility, better tolerated and stable metabolism. Moreover, it is
needed to design prodrugs such as phosphate ester of fluconazole (24),
voriconazole (30) and ravuconazole (34) [44,148,149]. A methyl group
on C-3 could enhance potency against moulds. The chiral form gives
special conformation that side-chain B moves in antiperiplanar to side-
chain A and also this methyl group fills the binding pocket of C-13 of
lanosterol [46,150]. Other substitutions such as CH (double bond with
C-3) and two methyl or two F (non-chiral C-3) have also the desired
activity. In some of the first generation structures, C-3 became an
oxygen, sulfur or NR2 (oxime and hydrazine) (miconazole (2) and its
derivations), which maintains antifungal activity and also conforma
tional restriction of structure with a ring on C-2 and C-3, such as
dioxalene (itraconazole (26) or ketoconazole (23)) or tetrahydrofuran
(posaconazole (31)); however, they do not enhance potency, or the
other pharmacokinetic properties and other groups such as ester,
amide, and carbamate are not appropriate for this replacement in an
tifungal activity, in contrast to antitrypanosome cruzi and anti
tubercular activity [151,152].
- Side chain A:
Side chain A in the structure that is always a halogenated phenyl, is
essential for inhibitory effect and appears to be located in the same
hydrophobic tunnel occupied with the 17-alkyl chain of lanosterol. It
Fig. 14. A: 3D structure of S. cerevisiae CYP51 complexed with fluconazole in the active site (PBD: 4WMZ). B: 3D structure of C. albicans CYP51 complexed with
oteseconazole in the active site (PBD: 5TZ1). Cyan dash line: metal coordination, Red dashes lines: water-mediated hydrogen bonding, green dash line: pi-stacking
interaction.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
16
17. has pi-pi stacking interactions with several residues like Y132 (a con
served amino acid among fungus). Substitutions of the phenyl ring in all
carbons are tolerated except in groups larger than chlorine in C-2 and C-
6 that have unfavorable steric clashes and cause a decrease in the
binding affinity of inhibitors in the active site. A greater potency is
obtained from fluorine atoms in C-2 and C-4. However, other large
bulky groups such as 4-fluorophenyl could be replaced in para position
and maintain the CYP51 inhibition activity of molecules [145,153].
- Side chain B:
Side chain B area is similar to that of the heme-binding group as we
could design potent and favorable pharmacokinetic properties only
with optimization in this side chain. Many medicinal chemistry studies
survey various substitutions in this side chain as can be seen in third-
generation and hybrid structures (Fig. 7 and Fig. 12) [112].
In general, a linker binds the side chain B to C-3 of tree atom linker,
and antifungal activity differs from several different types of linkers
here. Studies evaluating this area show that ether, thioether, carbon
(–CH2-, -CHR-, -CR2-), -NR2, -SO2-, heteroaromatic or hetroaliphatic
(e.g., piperazine, piperidine) rings are well-tolerated and are good types
of linkage, while amide, ester, and -NHR reduce antifungal activity
[154–156]. Substitutions binding to the structure via the mentioned
linkers could make several hydrophobic, steric and important H-bond
interactions in the deep binding cleft of target protein. Before any de
scription of this area, we divided azole drug into two groups based on
the size of the side chain, short-tail and long-tail structures.
For short tail structures, the linker may or may not have small
substitutions, like fluconazole (24), ravuconazole (34), and vor
iconazole (30) structures. Small hydrophobic, electron-rich and elec
tron-withdrawing groups (e.g., halogens, –CN, and halogenated het
eroaromatic rings) enhance potency in the ortho and para-position of a
phenyl or heteroaromatic ring attached to the linker, with probable
steric and hydrophobic interactions (both aromatic ring and its sub
stitution). In the voriconazole (30) case, fluorine on the pyrimidine ring
and Tyr122 of A. fumigatus form an H-bond interaction. Meta-position
substitutions are not favorable for activity [128,155].
For long-tail structures like itraconazole (26), posaconazole (31)
and VT-1598 (50), the para-position of a phenyl ring (like those for
short tail) could have a week H-bond acceptor substitution, preferably
oxygen (ether, carbonyl) and Nitrogen (NR2) that seems to form an H-
bond with some residue in the active site such as S-378 or H-374 and H-
377 (in the case of VT-1598 and oteseconazole) [147,155,156], and
also this H-bond acceptor group binds to another bulky aromatic group
with possible steric and van de waals interactions in the active site. In
the case of itraconazole-like drugs, a triazole-3-on group could enhance
pharmacokinetics of a compound. This area in the active site has en
ough space for further modification of structures to improve potency,
physicochemical and pharmacokinetic of desired antifungal com
pounds.
3. Concluding remarks and future directions
The number of hosts for invasive fungal infections is growing fast
due to an increase in circumstances that cause disturbed immune
function. In addition, the resistant rate of infective fungal spp to drugs
has improved with several known mechanisms like alteration in active
site residue by point mutations in ERG11 as the responsible gen for
CYP51, as well as ERG11 overexpression in fungal cells and MDR1
overexpression of efflux pump in fungi that may be concluded from
insufficient drug therapy. Thus, common drugs are ineffective and in
adequate to deal with this situation [157–160]. Although, four gen
erations of azoles as most diverse antifungal drugs are well developed
so far, the clinic has limited options for treatment. The options should
contain a wide spectrum action, parenteral or oral antifungal drug with
minimum drug-drug interaction and side-effects, effect on resistant
fungal infections, and acceptable pharmacokinetics properties. This
would never be achieved unless there are numerous studies by
Table 5
fungal CYP51, Drug − Target Complexes in PDB Databank (rcsb.org) as
Assessed in august 2019.
Organism Ligand PDB code Resolution (A⁰)
A.famigatus VNI 6CR2 2.38
A.famigatus VT-1598 5FRB 2.99
C. Albicans Itraconazole 5V5Z 2.9
C. Albicans Posaconazole 5FSA 2.86
C. Albicans VT-1161 5TZ1 2.0
C. Glabrata Itraconazole 5JLC 2.4
S. Cerevisiae Posaconazole 6E8Q 2.2
S. Cerevisiae Fluconazole 4WMZ 2.05
S. Cerevisiae VT-1161 5UL0 2.2
S. Cerevisiae Voriconazole 5HS1 2.1
S. Cerevisiae Lanosterol 4LXJ 1.9
S. Cerevisiae Itraconazole 5EQB 2.19
S. Cerevisiae (Y140F mutant) Itraconazole 4ZDY 2.02
S. Cerevisiae (Y140F mutant) Fluconazole 4ZDZ 2.3
S. Cerevisiae (Y140F mutant) Voriconazole 4ZE0 2.2
S. Cerevisiae (6464S mutant) Fluconazole 5ESY 2.15
S. Cerevisiae (G464S mutant) Itraconazole 5ESK 2.24
S. Cerevisiae (G73E mutant) Fluconazole 5ESF 2.25
S. Cerevisiae (G73E mutant) Itraconazole 5ESG 1.98
S. Cerevisiae (G73R mutant) Fluconazole 5ESE 2.2
S. Cerevisiae (G73W mutant) Itraconazole 5ESH 2.15
S. Cerevisiae (T3221 mutant) Itraconazole 5ESL 2.35
S. Cerevisiae (T3221 mutant) Fluconazole 5ESM 2.0
S. Cerevisiae (Y140Fmutant) Posaconazole 4ZE1 2.05
S. Cerevisiae (Y140H mutant) Itraconazole 4ZE2 2.3
S. Cerevisiae (Y140H mutant) Fluconazole 4ZE3 2.2
Fig. 15. Azole common structural model.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
17
18. medicinal chemistry scientist, the path started with fluconazole (24)
discovery and is on road with the newest 4th generation VT-1598 (50)
with improved characteristics. Albeit, in this way, azole is not the only
solution to the problem and identification of new targets are important
for efficient therapy. In this review, efforts were made to raise medic
inal chemists’ awareness toward azole from their ancestor chlormida
zole (1) to the most recent drug candidates in clinical trials and for the
first time introduce them in four generations with different new
structures. Moreover, hybrid antifungal agents as possible future gen
eration which attracted high interest, were presented. The structure
activity relationship according to valid and authentic information from
SAR studies were also reported. Even though, in each study on the novel
efficient structures the target-based information, based on new X-ray of
CYP51 of wild or resistant types are unavoidable, we inform researchers
of the recently uploaded information on the protein data bank (PDB,
rcsb.org) for discovery and development of new members in the azole
family.
Declaration of Competing Interest
The authors declared that there is no conflict of interest.
Acknowledgements
This work was supported by a grant from the research council of
Tehran University of Medical Sciences (Grant no: 98-02-33-42922).
Consent for publication
Not applicable.
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![Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
History of the development of antifungal azoles: A review on structures,
SAR, and mechanism of action
Mohammad Shafieia
, Lee Peytonb
, Mehrnoosh Hashemzadehc,⁎
, Alireza Foroumadia,⁎
a
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
b
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
c
University of Arizona college of medicine Phoenix and Pima college, Tucson, AZ, USA
A R T I C L E I N F O
Keywords:
Invasive fungal infection
Lanosterol 14α-demethylase
Azole
Structure activity relationship
Drug development
Molecular hybrids
A B S T R A C T
With the increasing risk of invasive and life threating fungal infections, there is now a great concern regarding
the lower discovery rate of antifungal drugs in comparison to antimicrobial agents. Drugs conventionally used in
clinics are not adequate enough to combat the increasing fungal infections, especially fungal forms resistant to
fluconazole. Among the limited antifungal agents in clinics, azoles have the largest number of drug candidates in
clinical trials and are partly marketed due to the particular focus of pharmaceutical companies and medicinal
scientific centers. With the rise in the number of papers on azole antifungal design and discovery, a more in-
depth understanding the most recent and authentic information about this class of drugs might be beneficial. To
this end, we for the first time summarized the state-of-the-art information about azole drugs, with a specific focus
on those in the pipelines of pharmaceutical companies, into four generations with regard to their structural
similarity. More importantly, this review highlights information on the structure activity relationship (SAR),
target description, hybrid antifungal agents as possible future generation, and other useful issues to streamline
research towards designing new efficient azole antifungal structures in future.
1. Introduction
1.1. Fungal infection
The Fungi kingdom is one of the most diverse organismal kingdoms
on the planet. Unlike the bacteria, fungi have eukaryotic cellular
functions, making them more closely related to human than bacteria
[1]. Out of more than two million fungi species, about 600 types are
known as human fungal pathogens, and only 3–4% of these species
account for > 99% of invasive fungal infection (IFI) [2]. These types of
fungal infections are often life-threatening and have a higher mortality
rate in comparison to superficial fungal infections, which are common
in human beings [3–5].
A particularly susceptible population for the development of IFIs are
individuals with compromised immune function such as those with
organ transplants and AIDS (acquired immune deficiency syndrome) as
well as those who are on prolonged immunosuppressive medications
such as corticosteroids. The patients with antibiotics, cancer che
motherapies, and the ones in intensive care units (ICU) are also at
greater risk to develop IFI [4]. This sheds some light on the opportu
nistic nature of fungal infection [6]. Over the last 30 years, IFIs in
creased with the rising number of the vulnerable population and an
nually caused 1–2 million deaths. The mortality rate was much greater
than that of malaria or tuberculosis [7–9]. > 90% of the deaths are
attributed to Candida and aspergillus species [10]. Candida species, in
cluding Candida albicans, Candida parapsilosis, Candida krusei, Candida
glabrata, and Candida tropicalis have emerged as invasive candidiasis,
whose mortality rate is increased up to 75% as they usually affect re
spiratory, gastrointestinal, skin, and urogenital tracts [11–13]. More
over, aspergillosis along with aspergillus spp. such as fumigatus, flavus,
niger, terreus, and parasiticus mainly affect external ear, lungs, eye, and
brain, with a mortality rate of 50–90% [14].
Although Fungi infection is the first scientifically reported or
ganism-derived disease, prior to bacterial infections [15], antifungal
drug discovery has mightily lagged behind antibacterial chemotherapy,
resulting in one of the main problems with targeting fungal species, i.e.
the eukaryotic nature of fungi makes them intrinsically difficult to be
targeted without the probable toxic effects of antifungal drugs in
https://doi.org/10.1016/j.bioorg.2020.104240
Received 9 June 2020; Received in revised form 17 July 2020; Accepted 11 August 2020
⁎
Corresponding authors at: University of Arizona college of medicine Phoenix and Pima college, Tucson, Arizona, USA. (Mehrnoosh Hashemzadeh). Department of
Medicinal Chemistry, Faculty of Pharmacy & The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran (Alireza
Foroumadi).
E-mail addresses: mhashemz1@yahoo.com (M. Hashemzadeh), aforoumadi@yahoo.com (A. Foroumadi).
Bioorganic Chemistry 104 (2020) 104240
Available online 28 August 2020
0045-2068/ © 2020 Elsevier Inc. All rights reserved.
T](https://image.slidesharecdn.com/shafiei2020-211203080231/85/Shafiei2020-1-320.jpg)
![human cells [15]. Accordingly, the development of selective antifungal
drugs with lower side-effect is a hotbed of research among medicinal
chemists [16].
1.2. Current medications
Currently, there are several well-known mechanisms to treat sys
temic and superficial fungal infections using roughly 40 branded anti
fungal drugs in the market and the other drug candidates in clinical
trials, which adopt new or convenient mechanisms to target fungi
(Fig. 1) [2,17–20].
Interestingly, the previous studies have introduced some new tar
gets to combat fungal infections, hoping that the emerging strategies
may yield the treatment for resistant fungal infections (Fig. 2) [21–24].
Despite new research and development in this field, there is still no
new approved drug for the more recent strategies. As shown in Figs. 1-
14-α demethylase inhibitors (azoles) are the most important and the
most approved clinical candidate drugs.
According to previous studies, classified azoles cover several char
acteristics of the most potent antifungals. Over the past half-century,
this family has had a significant effect on controlling invasive and su
perficial fungal infections. Their newer generation further increased
highly desired properties such as safety, lower risk of drug-drug inter
actions, proper pharmacokinetics, and improved activity spectrum
[25–27].
With the large number of azole antifungals in the clinics and in
experimental medicinal chemistry institutions, keeping track of pro
mising molecules that are under development is challenging for the
researchers in the field. In this paper, we provide a comprehensive
review and an update of all approved and clinical candidates of azole
antifungal drugs, as azole pedigree in regard to their structural simi
larities. Herein, the description of the target, salient medicinal chem
istry points regarding azole structures (SAR), and the selectivity of these
structures for the concerned target are discussed. Furthermore, hybrid
antifungal agents as a prospective future generation are introduced to
pave the way for developing new efficient azole antifungal structures in
the future.
2. Azole family
2.1. History and pedigree
The first report on the antifungal activity of an azole compound was
presented by Woolley (1944), a serendipitous discovery that declared
the antimycotic effect of benzimidazole moiety for the first time [28].
Afterwards, several other researchers indicated other azole antifungal
structures such phenethylimidazole [29] and substituted benzimida
zoles [30]; however, none of these reports led to the development a
drug until 1958, when chlormidazole (1, Fig. 3) was introduced, the
first azole drug marketed by Chemie Grünenthal. Accordingly, chlor
midazole was the pioneer of enormous research on azole antifungal
activities. Currently, there are about 40 azole-containing drugs and
drug candidates, which could be classified into more than three gen
erations [15,31,32]. This field of study is still of great interest.
2.1.1. First generation
The first generation of azole family emerged with the introduction
of three compounds: clotrimazole (13) from Bayer AG in 1969,
Janssen’s miconazole (2) at the same time, and later econazole (3) in
1974. These three drugs were launched as topical antifungal agents
making azoles an indispensable asset in treating fungal infections[15].
Following the discovery of these early structures, several analog com
pounds are marketed, which can be categorized into the first-generation
group due to their similar physiochemical properties and indications in
treating superficial fungal infections such as dermatomycoses, tinea
versicolor, cutaneous, and vaginal candidiasis as well as topical for
mulations. Considering their structures, they have similar imidazole-
contained backbone and could be further sub-divided into three cate
gories: miconazole-based structures, clotrimazole- based structures, and
vinyl-imidazole derivations, as shown in Fig. 4.
Fig. 1. Antifungal drugs. the number of approved and clinical trial agents are summarized.
M. Shafiei, et al. Bioorganic Chemistry 104 (2020) 104240
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