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2 Fungal Fighters: A Comprehensive Guide to Antifungal Therapies of the Past…
47
Fig. 2.1 Showing the different modications of Echinocandins
Caspofungin In the year 1989, Merck & Co. Research Laboratories (USA)
reported Pneumocandin A0 and Pneumocandin B0 as metabolites of the species
Glarea lozoyensis having antimycotic activity (Fromtling and Abruzzo 1989;
Schwartz et al. 1989; Wichmann et al. 1989). Unlike Echinocandin-B,
Pneumocandin-B0 is a cyclic hexapeptide made up of 4,5-dihydroxyornithine, threonine, two 4-hydroxyproline, 3-hydroxylamine, 3,4-dihydroxyhomotyrosine, and a
48
B. Biswas and A. Thakur
10,12-dimethyl-myristoyl α-acylated with the 4,5-dihydroxyornithine. Later, they
made derivatives of Pneumocandin B0 by modifying 3-hydroxyglutamine to
3-hydroxyornithine and also hemiaminal group of C5 of 4,5-dihydroxyornithine
was replaced with ethylene diamine (Balkovec etal. 2014; Luthra etal. 2014). This
was the drug candidate caspofungin. The change in the Pneumocandin-B0 structure
increased the solubility of the drug in water and also increased its binding to the
membrane due to the electrostatic interaction of ethanolamine with the phospholipids (Bouffard etal. 1994). Caspofungin was approved as an antifungal for adults in
2001in the US (Balkovec etal. 2014). In July 2008, it was approved for use amongst
children in 3months of age criteria (Chen etal. 2011).
Micafungin The story of micafungin begins with the screening of broth from 6000
different cultures that had antifungal effects in Japan at the Fujisawa Pharmaceutical
Co., Ltd. in 1989. Three related compounds were shortlisted (viz. FR901379,
FR901381, and FR901382). All the compounds have high water solubility and high
antifungal activity against Candida spp. (Tomishima et al. 2008a). However,
FR901379 production was higher than that of other analogs, reaching up to
4000mg/L (Jiang etal. 2024). FR901379 is structurally the same as Echinocandin-B
but has a sodium sulfate attached to its 3,4-dihydroxyhomotyrosine which is the
reason for its higher solubility when compared to Echinocandin-B. Even though
highly water soluble, it struggled with the same problem as echinocandin B which
is the hemolytic property. The palmitoyl acyl chain attached to the
4,5- dihydroxyornithine caused the hemolysis as well as lysis of reticulocytes
(Tomishima etal. 2008b). So, an isoxazole ring between two benzene ring systems
with optimal acyl side chain length would give a Clogp=6 containing was reacylated instead of palmitoyl acyl chain to optimize the lead of FR901379 to achieve the
specicity for the antifungal activity and lesser hemolytic damage (Hashimoto
2009). This gave rise to the compound FK463 later known as micafungin.
Micafungin was approved for clinical use after it passed the clinical phase trials in
March of the year 2005.
Second-Generation Echinocandin
Rezafungin Anidulafungin was further modied to form Rezafungin. Hemiaminal
region of C5 of 4,5-dihydroxyornithine was replaced with choline amine ether
(Lakota etal. 2018). This change increased the solubility and serum stability from
10% in anidulafungin to 94% in Rezafungin and also increased the bioavailability
(Garcia-Effron 2020). Rezafungin was approved as an IV injection in adults in
March 2023 (Fig.2.1).
2.2.1.3 Other Cell Wall Inhibitors
Lufenuron Lufenuron is a chitin synthase inhibitor initially used to treat ea infec-
tion (Papich 2016). Recently, it was also tested to treat dermatomycoses for veterinary use in cats and dogs (Ben-Ziony and Arzi 2000). Its human usage is not
approved yet.
2 Fungal Fighters: A Comprehensive Guide to Antifungal Therapies of the Past…
49
Carvacrol Carvacrol is a monoterpene phenol found in essential oils of many
plants. In fungus like A. alternata, it has been shown to decrease β-glucans and
chitin by reducing β-glucan synthase and chitin synthase activity (Zhao etal. 2023).
Also, in C. albicans, it is shown that carvacrol causes Ca2+/calcineurin-dependent
apoptosis of the fungus (Niu etal. 2020). Its use is still conned to invitro, and its
human usage is not approved yet.
Nikkomycin-Z Nikkomycin-Z which was discovered in the 1970s is a nucleoside
antifungal (Dähn etal. 1976). It has a pretty low IC50 value of 4μg/ml against
Candida albicans. It works by a mechanism of competitive inhibition to inhibit the
fungal chitin synthase (Nix etal. 2009; Ren etal. 2022). It has nished the clinical
phase 1 trial and has been shown that 250–2000 mg is safe to administer
(Larwood 2020).
Polyoxins It has a similar structure just like Nikkomycin-Z and it is also a competi-
tive inhibitor of the chitin synthase. It competes with UDP-glucose for its binding
with the chitin synthase (Zhang and Miller 1999). Its human usage is not
approved yet.
2.2.2 Sterols Biosynthesis Synthesis andCell Membrane
Targeting Drugs
Sterols in the membrane are the regulators of important biological functions such as
cell signalling and also help to sustain the domain structure of cell membranes
which is why they are considered as membrane reinforcers. It is also responsible for
hosting membrane proteins and retaining their structures.
Ergosterol synthesis starts by the uptake of squalene. Squalene is a triterpenoid
that is synthesized by the mevalonate pathway. The mevalonate pathway goes as
follows (Lu etal. 2022). Mevalonate pathway is an important biological pathway
that starts with acetyl CoA and acetoacetyl CoA.This pathway gives rise to isoprenoids, sterols, ubiquinone, and dolichols. Acetyl CoA from glycolysis is converted to
acetoacetyl CoA by thiolase 2 that converts acetyl CoA to acetoacetyl CoA.In the
cytosol, this acetoacetyl CoA is further converted to mevalonate- 5- pyrophosphate
(Cao etal. 2020). One of the products of this mevalonate pathway is isopentinyl
pyrophosphate which is uptaken by endoplasmic reticulum and regulated by NUS1
(Grabińska etal. 2017). It is converted to farnesyl- pyrophosphate and is the starting
compound for sesquiterpene synthesis. An alternate pathway starts when Erg9 protein of the ergosterol pathway converts farnesyl pyrophosphate to squalene using
NADH. This squalene is the starting molecule of the ergosterol biosynthetic
pathway.
Ergosterol synthesis start as follows (Sanglard etal. 2003). The rst enzyme of
the ergosterol pathway is Erg1 or squalene epoxidase that converts squalene to
50
B. Biswas and A. Thakur
squalene-2,3-epoxide. This enzyme is the target of allylamine class of drugs. The
squalene epoxide is then converted to lanosterol by Erg7 or lanosterol synthase. This
lanosterol is further demethylated and reduced by lanosterol 14-α-demethylase
(Erg11) and C-14 sterol reductase (Erg24) respectively. A mutation in the Erg11 gene
promotes the resistance to imidazole and triazoles. Erg11 is the target of triazoles and
imidazoles. However, 4-methyl zymosterol carboxylate is produced by the action of
C-4 sterol oxidase (Erg25) that oxidizes one of the methyl groups present in the
fourth position of 14-demethyl lanosterol to carboxyl group producing 4-methyl
zymosterol. After this, the combined work of C-3 sterol dehydrogenase (Erg26),
3-keto sterol reductase (Erg27) helps in the synthesis of Zymosterol. Delta(24)-sterol
C-methyltransferase (Erg6) transfers a methyl group to zymosterol to produce fecosterol. This Erg6 is also found to be mutated along with HMG-CoA reductase of the
mevalonate pathway in uconazole resistance. An isomerase C-8 sterol isomerase
(Erg2) produces episterol. C-5 sterol desaturase (Erg3) catalyzes the C-5(6) double
bond formation of episterol to dehydroepisterol. This Erg3 is found truncated or
nonfunctional in azole resistances since this enzyme also causes the formation of the
toxic sterol 14α methyl 3,6 diol in the presence of azoles. Finally, Delta (24(28))-sterol reductase (Erg4), C-22 sterol desaturase (Erg5) catalyzes to form ergosterol.
Ergosterol formed is the target of polyene class of drug. Often due to the mutation of
Erg3 and Erg6 due to azole resistance, it often confers cross resistance to polyenes.
The enzymes of these pathways are dependent on oxygen and Fe (II) clusters and
heme cores. Erg1 requires oxygen for oxidation of squalene. Erg11 and Erg5
requires heme cores and oxygen for its functioning. Erg25 and Erg3 requires Fe(II)
cluster and oxygen for its functioning.
2.2.2.1 Azoles
Before 1981, there was a very limited option for treating invasive fungal infections
with the advent of azoles the scenario changed. Ketoconazole was the rst drug of
azole class discovered. Azole classes of antifungals are divided into two main categories viz. imidazole and triazoles.
Imidazole
Imidazole class of drug contains a heterocyclic ring of three carbons and two nitrogens called the imidazole ring. This imidazole ring was rst reported by a German
chemist Henrich Debus in 1887 (Siwach and Verma 2021). The discovery of the
imidazole class of antibiotic began when Woolley etal. were trying to synthesize
derivatives of pyrithiamine biologically important compounds that would compete
with vitamins to produce vitamin deciency specically thiamine deciency in animals and microorganisms (Woolley and White 1943). Contemporarily, Goodman
etal. also showed benzimidazole a biotin analogue caused death of the organism
(Goodman etal. 1943). Woolley looking at the structure thought it was due to biotin
deciency but later proved that instead it is due to competition with aminopurines,
adenine, and guanine (Woolley 1944). The problem with benzimidazole is that it
caused anesthesia in animals (Woolley 1944). The rst derivative made was chlormidazole in 1958 by attaching a chlorobenzene molecule to the rst nitrogen of the
2 Fungal Fighters: A Comprehensive Guide to Antifungal Therapies of the Past…
51
benzimidazole and was used for topical application against yeast and other fungal
infection (Holt 1976).The mechanism of action of imidazole in the ergosterol pathway is shown in the (Fig.2.2)
Clotrimazole Clotrimazole is an imidazole class of antifungal. Instead of using the
benzimidazole ring, the hydrogen of the methyl group attached to imidazole is substituted by a chlorobenzene and two benzene rings. Thus, another imidazole was
discovered which is called as clotrimazole. Clotrimazole is more fat soluble than
water (Holt 1976). Also, it is mostly used as a topical agent, vulvovaginal, and oral
thrush candidiasis since bioavailability is low for systemic usage (Spitzer and
Wiederhold 2018). Clotrimazole came into human use by 1958 (Sawyer etal. 1975).
Bifonazole Bifonazole is an imidazole derivative that is formed by substituting the
three hydrogens with imidazole, phenyl, and biphenyl groups. It blocks CYP51 or
Erg11 of the ergosterol pathway and HMG-reductase of the mevalonate pathway to
block sterol synthesis (Berg et al. 1984). Bifonazole was approved for medical
usage in 1983.
Miconazole Miconazole is a phenethyl imidazole derivative which was rst syn-
thesized in 1969. The methyl imidazole group is attached to 1-methyl-2,4dichlorobenzene, and nally, another 1-methyl-2,4-dichlorobenzene is ether linked
to the previous. An addition of halogens to the benzene side chains increased its
afnity towards C. albicans and the MIC value lowered signicantly. Although it
remained less bioavailable like clotrimazole, it worked better than clotrimazole
topically since it had more afnity towards Candida. Thus, this drug was licensed
under the generic name miconazole. It was approved for human administration
in 1978.
Fig. 2.2 Mechanism of action for the cell membrane targeting drugs
52
B. Biswas and A. Thakur
Isoconazole and Econazole At the time of research and development of the
miconazole, few other derivatives of the same phenethyl imidazole class showed
promising results (Heeres etal. 2010). Amongst them are the isoconazole and econazole. Isoconazole is derived by changing the position of the halogen groups in
O-linked 1-methyl-2,4-dichlorobenzene to 5-methyl-4,6-dichlorobenzene.
Econazole is produced by replacing ether linked 1-methyl-2,4-chlorobenzene to
5-methyl-2-chlorobenzene. Isoconazole was approved for medical usage in the year
1979. It also had less bioavailability which was approved to be used in combination
with corticosteroid diuorocortolone to increase its bioavailability (Veraldi 2013).
Econazole was approved for medical usage in the year 1974. FDA approved the
usage econazole nitrate cream in November 2013.
Terconazole and Ketoconazole Imidazolyl dioxolanes derivatives gave rise to terconazole and ketoconazole. However, a 1-benzyl-piperazine is ester linked to imidazolyl dioxolanes. The sec-butyl attached to 1-benzyl-piperazine is found in
terconazole and the methylketone group is found in ketoconazole. While terconazole is used for topical use, ketoconazole is the rst imidazole to be used for oral
and systemic use. Terconazole was approved for medical use in 1987in the form of
cream formulation. Ketoconazole was used and approved for medical use in the
year 1981. Furthermore, this terconazole was used to develop itraconazole.
Other Derivatives ofIsoconazole andEconazole
Tioconazole 2,4-Dichlorobenzene in the structure of miconazole was replaced
with a 2-(3-chloro-thienyl)-methyl moiety to give tioconazole. It was approved for
medical usage in the year 1982.
Oxiconazole Oxiconazole was produced by ketoxime, a linkage linking
4-methyl- 1,3-dichlorobenzene with methyl imidazole group and 1-methyl-2,4dichlorobenzene moieties in the miconazole structure. It was approved for medical
usage in the year 1983.
Sertaconazole 2,4-Dichlorobenzyl group in miconazole was replaced with
3-(7-chlorobenzothiophene)-methyl group gave sertaconazole. It was approved for
medical usage in the year 2003.
Fenticonazole Fenticonazole was synthesized by modifying econazole molecule.
The ether linked 5-methyl-2-chlorobenzene was replaced by the a large phenylthio.
It was approved for medical usage in the year 2022in India. It is not yet approved
in the USA and some other European countries. Replacement of the oxygen by a
sulfur in the econazole structure led to the discovery of sulconazole. It was approved
for medical usage in the year 2008in India. It is not yet approved in the USA and
some other European countries.
2 Fungal Fighters: A Comprehensive Guide to Antifungal Therapies of the Past…
53
Butoconazole Elongating the distance between the aryl group and the imidazole
ring led to the discovery of a newer imidazole derivative called 1-(arylbutyl)-imidazole derivative and the compound was named as butoconazole. It was approved for
medical usage in the year 2023in India. It is not yet approved in the USA and some
other European countries.
Climbazole Climbazole is a modication of econazole and the 1-methyl-2,4-
chlorobenzyl group is replaced by an ester linked tertiary butyl group. Climbazole
was approved for medical use in the year 2011.
Luliconazole and Eberconazole Luliconazole and eberconazole are the newest
recruits of the imidazole family. Luliconazole contains a 1,3 dithiole group connecting 1-methyl-2,4-chlorobenzene and methyl imidazole. The methyl imidazole of
eberconazole connects a benzyl and dichlorobenzyl group to their meta position.
The aromatic systems are again connected to each other via a methyl group connected to their ortho position. Luliconazole was approved for medical use in
November, 2013. Eberconazole is approved for medical use in Spain in the
year 2015.
Most of the imidazoles are used in the form of cream for topical application or
local application like vaginal thrush or oral thrush treatment. However, imidazoles
are prone to acid hydrolysis in stomach and low systemic bioavailability.
Triazole
Triazole is a ve-membered heterocyclic aromatic ring system that contains three
nitrogen. Triazole was discovered in 1885 by Bladin (Bladin 1885). The heterocyclic structures of triazoles are found to form many weak interactions with the receptors such as hydrogen bonds and Vander Waal interaction with enzymes in biological
systems (Matin etal. 2022).
Second-Generation Azole
Fluconazole Fluconazole is the rst in class triazole. Here, instead of two nitrogen
imidazole rings, a three nitrogen triazole ring was used which made the drug more
stable. The imidazole ring of ketoconazole for oral usage is used to get acid hydrolyzed; on the other hand, the triazole group are less likely to get acid hydrolyzed
(Bozorov etal. 2019). Thus, making it orally stable. The uconazole structure have
two triazoles attached to a hydroxyl group, and unlike the imidazole, previously had
chlorobenzene uconazole used uorobenzyl groups. The uorines provided more
stable binding with the iron atom in heme in the CYP51 (Sagatova etal. 2015).Thus,
it also targets ERG11 just like the imidazoles and abrogates the ergosterol biosynthetic pathway (Fig. 2.2). Fluconazole was approved for human usage in the
year 1990.
54
B. Biswas and A. Thakur
Itraconazole Itraconazole is the modied ketoconazole. The imidazole groups are
replaced by triazole. Also, itraconazole uses the same side chain as ketoconazole
with a modication of 1-benzyl-4-isobutyl-5-ketotriazole attached to the piperazine
instead of methyl ketone group, 5-keto triazole. Itraconazole almost have equal
activity against candidiasis. Itraconazole was approved for medical use in the year
1992. The triazole group increased its oral stability and the change in the ketone
group increased its binding to the CYP51 also, increased its bioavailability (Marr
etal. 2004; Staśkiewicz etal. 2021). Patients with uconazole-resistant candidiasis
can be treated with itraconazole (Partha etal. 2022). Itraconazole was approved for
human usage in the year 1992.
Third-Generation Azole
Third-generation azoles are modied versions of the second-generation azole.
Voriconazole Voriconazole is the modied version of uconazole. One of the tri-
azole groups is replaced by uorinated methyl imidazole. Thus, increasing afnity
towards heme moiety of CYP51. Patients suffering from uconazole-resistant candidiasis can be treated with voriconazole (Partha etal. 2022). Voriconazole was
approved for human usage in the year 2002.
Posaconazole Posaconazole uses the structure of itraconazole and the isobutyl
group is replaced with Pentan-2-ol. Attaching pentan-2-ol increases the
bioavailability, solubility, and resistant to metabolism by cytochrome P450 (Chen
etal. 2020). Posaconazole was approved for human usage in the year 2006.
Enaconazole 4-Methylene-1-ethyl-piperadine moiety was used instead of a tri-
azole moiety. This modication promotes binding but is readily metabolized in the
body, thus reducing bioavailability. Thus, its usage is conned to topical usage
(Gupta etal. 2020).
Isavuconazole, Ravuconazole, and Albaconazole All of them uses the same
structural backbone of uconazole. Ravuconazole uses 4-(p-cyanophenyl)-1,3-
thiazol- 2-yl instead of one of the triazole group. Isavuconazole uses
4-(p-cyanophenyl)-1,3-thiazol-2-yl instead of one of the triazole groups and 2,5
diuorophenyl group instead of the 2,4 diuorophenyl group. Albaconazole uses
7-chloro-3-ethylquinazolinone moiety instead of a triazole moiety. These modications to the drug increase it binding to the CYP51 and their bioavailability
(Pasqualotto etal. 2010). Isavuconazole was approved in 2015, and Ravuconazole
is currently approved in Japan in the year 2018. Fosravuconazole is a phosphate
ester of prodrug that promotes bioavailability of ravuconazole (Ohwada etal. 2002;
Ueda etal. 2003). Albaconazole is under clinical phase 2 trial.
2 Fungal Fighters: A Comprehensive Guide to Antifungal Therapies of the Past…
55
2.2.2.2 Polyenes
Polyenes are a group of polyunsaturated aliphatic hydrocarbons that contains at
least three alternating double bonds (C=C) and a single (C–C) single bond and also
(C≡C) triple bonds (Nigam 2021). Polyenes have optical properties mostly because
of the alternating double bonds that make polyenes absorb in the UV region and
emit in the visual spectrum. Polyenes are antibiotics that bind to ergosterol and
cause cell membranes to leak. Polyenes interact with ergosterol through hydrophobic and electrostatic interactions, forming a complex that makes the membranes
leaky (Carolus etal. 2020). Basically, these plucks out the sterols while leaking out
the rest of the membrane. These macrolides with many hydroxyl groups binds to
ergosterolas shown in (Fig.2.2) and forms small pore that causes loss of small ions
(Bardal et al. 2011). Although it binds to ergosterol, it also has cross reactivity
against cholesterol (Bardal etal. 2011). On a broader aspect, polyenes are divided
into tetraenes, pentaenes, hexaenes, and heptaenes (Lampen etal. 1960).
Nystatin Nystatin is the rst polyene that was discovered, also it is the rst suc-
cessful antifungal that was approved for human use (Dixon and Walsh 1996). It is a
tetraene and was rst name as fungicidin. It has a broad-spectrum antifungal activity. Nystatin is extracted from Streptomyces noursei (Brautaset etal. 2000). Nystatin
inhibits C. albicans at a concentration of 3μg/ml. It was also very toxic for the host
for systemic administration and, as a result, was used for topical application.
Nystatin was approved for medical use in the year 1971.
Natamycin Natamycin is a polyene isolated from Streptomyces natalensis and is
used to treat supercial infection. It is a pentaene that has very low absorption orally
and is thus used topically in eye infection, nail infection, and vaginal and oral thrush
candidiasis (Birch and Sibley 2017). It was approved for medical use in the
year 1978.
Amphotericin-B Amphotericin-B is the third polyene that was discovered. It is a
heptaene extracted from Streptomyces nodosus (Zhang etal. 2020). It is the most
potent antifungal capable of inhibiting candida at a very low concentration (Spierer
etal. 2015). Amphotericin-B is a polyene that has systemic absorption and higher
bioavailability (Wang etal. 2021). It was approved in the year 1997.
Candicidin D Candicidin-D is a relatively newer antifungal and was isolated from
Streptomyces griseus (Szwarc etal. 2015). Candicidin-D is most active against the
Candida genus of fungus with MIC of 5ng/ml. Candicidin is approved for medical
use in the year 1964.
Candidin Candidin was isolated from S. viridiavus, and it is similar in property
like Amphotericin-B (Taber etal. 1954).
56
B. Biswas and A. Thakur
Trichomycin It is also a heptaene isolated from S. hachijoensis. It is very effective
in the treatment of vulvovaginal candidiasis and is the oldest used polyene.
Patricin Patricin is a heptaene that has two forms such as Patricin-A and
Patricin-B.Patricin-A is also known as vacidin, and Patricin-B is also known as
gentamicin. Both of them have signicantly high antifungal activity with MICs
around 0.25μg/ml (Borzyszkowska-Bukowska etal. 2021).
Hamycin It was discovered in India from S. pimprina.
Other Polyene Under Development
NPP-A1 Nystatin like Pseudonocardia polyene (NPP) B1 is a disaccharide-
containing tetraene macrolide. This drug has lower hemotoxicity than amphotericin- B but gives same hepatotoxicity like amphotericin B and also this drug has a
half-life of 36.25min (Kim etal. 2018). It is currently under development.
Aspernidulgene A1 It is a newest polyene under development and is isolated from
Aspergillus nidulans (Lin etal. 2019).
2.2.2.3 Allylamines
Allylamines are unsaturated amines that blocks the rst step of ergosterol biosynthetic pathway. It is a competitive inhibitor of squalene epoxidase or Erg1
gene(Fig.2.2). It competes with squalene for binding with Erg1 (Hammoudi Halat
etal. 2022).
Naftine Naftine is the rst in class of this antifungal. The discovery of naftine
was accidental. It was made during the synthesis of a CNS active agent in Sandoz
institute Vienna (Mieth 1990). Just like regular checking of any compound’s antimicrobial efcacy, it was also checked and was found to be effective against fungi. It
was comparable to the antimycotic compound clotrimazole and became best choice
of drug to be used against C. albicans with MIC around 0.2–3μg/ml (Schaude etal.
1987). It contains a 1-methyl-aminomethyl naphthalene backbone. The side chain is
phenylpropene.
Terbinane Terbinane is a modication of naftine. The backbone remained the
same; the modication happened in the side chain. Instead of the benzyl group, the
propene was ligated with an additional triple bond (the acetylene group), and the
addition of a isobutane group increased its activity against fungus invitro. Although
the invivo activity was similar, it is used for the topical application. Terbinane is
10–100 times more active than naftine (Gupta et al. 2021). Terbinane was
approved for medical use in the year 1992.