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Review
. 2022 Nov 17;15(11):1427.
doi: 10.3390/ph15111427.

New Antifungal Agents with Azole Moieties

Melissa Martins Teixeira  1   2   3 , Diogo Teixeira Carvalho  1   4 , Emília Sousa  1   3 , Eugénia Pinto  2   3
Affiliations
Review

New Antifungal Agents with Azole Moieties

Melissa Martins Teixeira et al. Pharmaceuticals (Basel). .

Abstract

Fungal conditions affect a multitude of people worldwide, leading to increased hospitalization and mortality rates, and the need for novel antifungals is emerging with the rise of resistance and immunocompromised patients. Continuous use of azole drugs, which act by inhibiting the fungal CYP51, involved in the synthesis of ergosterol, essential to the fungal cell membrane, has enhanced the resistance and tolerance of some fungal strains to treatment, thereby limiting the arsenal of available drugs. The goal of this review is to gather literature information on new promising azole developments in clinical trials, with in vitro and in vivo results against fungal strains, and complementary assays, such as toxicity, susceptibility assays, docking studies, among others. Several molecules are reviewed as novel azole structures in clinical trials and with recent/imminent approvals, as well as other innovative molecules with promising antifungal activity. Structure-activity relationship (SAR) studies are displayed whenever possible. The azole moiety is brought over as a privileged structure, with multiple different compounds emerging with distinct pharmacophores and SAR. Particularly, 1,2,3-triazole natural product conjugates emerged in the last years, presenting promising antifungal activity and a broad spectrum against various fungi.

Keywords: antifungal drugs; azoles; new developments.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of pyrrole, the simplest azole, as well as azole rings containing nitrogen only, nitrogen and oxygen, and nitrogen and sulphur [10,11].
Figure 2
Figure 2
Structures and approval dates of imidazole antifungal drugs [9,17].
Figure 3
Figure 3
Structures and approval dates of triazole antifungal drugs [9,19,21].
Figure 4
Figure 4
Summarized synthesis of ergosterol, the fungal sterol, and detailed steps of CYP51 conversion of lanosterol to 14α-demethyl lanosterol (Adapted from Peyton, 2015) [8,23].
Figure 5
Figure 5
(a) Representation of the interaction of fluconazole (in green), a known triazole antifungal drug, with the heme group (in red) in the active site of CYP51 from Saccharomyces cerevisiae; (b) Representation of the interaction of VT-1161 (in green), a tetrazole antifungal agent, with the heme group (in red) in the active site of CYP51 from Candida albicans. ChemBio3D was used to visualize (PDB 4WMZ and PDB 5TZ, respectively) [25,26].
Figure 6
Figure 6
Chemical structures of luliconazole (1) and lanoconazole (2) [30].
Figure 7
Figure 7
Chemical structure of isavuconazole (3), a novel triazole antifungal agent [41].
Figure 8
Figure 8
Chemical structure of iodiconazole (4), a novel triazole antifungal [55].
Figure 9
Figure 9
Chemical structures of compounds 5, 6, and 7, novel triazole agents derived from iodiconazole (4), and respective SAR [57].
Figure 10
Figure 10
Chemical structure of albaconazole (8) [5].
Figure 11
Figure 11
Chemical structures for compounds 9–14, novel triazoles derived from albaconazole (8), and respective SAR [57].
Figure 12
Figure 12
Chemical structure for compound 15, novel triazole molecule designed based on albaconazole (8) [60].
Figure 13
Figure 13
Chemical structure of PC945 (16), a novel triazole molecule [62].
Figure 14
Figure 14
Chemical structures of VT-1161 (17) and VT-1129 (18) [72].
Figure 15
Figure 15
Chemical structure of VT-1598 (19), a next-generation tetrazole hybrid [62].
Figure 16
Figure 16
Chemical structure of the tested triazole compounds [96].
Figure 17
Figure 17
Scaffold for the difluoro- (20) and dichloro- (21) phenylethyl-triazole series, as well as the structure for compound 21a and respective SAR [97].
Figure 18
Figure 18
Chemical structures for compounds 22–29, and respective SAR [98].
Figure 19
Figure 19
Chemical structures for compounds 30–32 and SAR for the phenyl ring [99].
Figure 20
Figure 20
Chemical structures of triazole-thiazolidinedione hybrid compounds 33–35 [100].
Figure 21
Figure 21
Chemical structure of 5-flucytosine and fluconazole hybrid (36) and of scaffolds of aryl series (37) and halobenzyl series (38), and particularly of compound 38a, and SAR for the two series [101].
Figure 22
Figure 22
Chemical structures of compounds 39a–c and 40a–c and SAR [102].
Figure 23
Figure 23
Chemical structures of compounds 41 and 42, and SAR [103].
Figure 24
Figure 24
Chemical structures of 43–45 and SAR [104].
Figure 25
Figure 25
Chemical structures for compounds 46–49 and SAR [105].
Figure 26
Figure 26
Chemical structures for compounds 50a, 51a–c, and 52a–c [106].
Figure 27
Figure 27
Impact of different moieties on the antifungal activity of the represented scaffold [104,105,106,107].
Figure 28
Figure 28
Chemical structure of compound 53 and SAR for this series of tetrazole-tetrazole hybrids [108].
Figure 29
Figure 29
Chemical structure of compound 54 [109].
Figure 30
Figure 30
Chemical structures of compounds 55 and 56, and toxicity SAR [110].
Figure 31
Figure 31
Chemical structures of compounds 57–59 and SAR regarding the R2 substituents [111].
Figure 32
Figure 32
Chemical structures of 60 and 61 [112].
Figure 33
Figure 33
Chemical structures of compounds 62–64 [113].
Figure 34
Figure 34
Chemical structures of compounds 65a–b and 66a–b, and SAR [114].
Figure 35
Figure 35
Chemical structures of compounds 67 and 68 and SAR against C. albicans and A. niger [115].
Figure 36
Figure 36
Chemical structures of 2,5-isomers 69a–c and 1,5-isomers 70a–c and SAR [116].
Figure 37
Figure 37
Chemical structures of compounds 71 and 72a–b, and SAR [117].
Figure 38
Figure 38
Chemical structures of compounds 73–75, and SAR regarding the phenyl ring [118].
Figure 39
Figure 39
Chemical structures for compounds 76–79, and SAR [119].
Figure 40
Figure 40
Chemical structures for compounds 80 and 81, and SAR regarding the phenyl ring [120].
Figure 41
Figure 41
Chemical structures of compounds 82–84 [121].
Figure 42
Figure 42
Chemical structure of the tetrazole-pyrazole compounds and SAR [107].
Figure 43
Figure 43
Chemical structures of compound 85–88, and SAR [123].
Figure 44
Figure 44
Chemical structure for compounds 89–92, and SAR for the tested series of azole-carbodithioate hybrids [124].
Figure 45
Figure 45
Chemical structure of compounds 93a–b and 94, as well as SAR for the Candida species [125].
Figure 46
Figure 46
Chemical structures of 95a–c [127].
Figure 47
Figure 47
Chemical structures of compounds 96 and 97 [131].
Figure 48
Figure 48
Chemical structures of compounds 98 and 99, and SAR [133].
Figure 49
Figure 49
Chemical structure of compounds 100–103 [134].
Figure 50
Figure 50
Chemical structure for compounds 104 and 105 [135].
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