Novel triazole alcohol antifungals derived from fluconazole: design, synthesis, and biological activity

Abstract

A series of new triazole alcohol antifungals were designed by replacing one of the triazolyl moiety from fluconazole with a distinct 4-amino-3-mercapto-1,2,4-triazole motif, which is found in some antimicrobial agents. The antimicrobial susceptibility testing of target compounds demonstrated that the direct analogs of fluconazole (difluorophenethyl-triazoles) were less active against fungi, while compound 10h containing dichloro substitutions on both phenyl rings of the molecule had potent activity against yeasts including Candida albicans (four strains) and Cryptococcus neoformans (MICs = 2-8 μg/mL). Also, compound 10h was active against Candida parapsilosis, Epidermophyton floccosum, and Trichophyton mentagrophytes, while it showed no activity against Gram-positive and Gram-negative bacteria. Finally, a molecular docking study suggested that compound 10h interacts suitably with lanosterol 14α-demethylase, which is the key enzyme in ergosterol biosynthesis.

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungusCryptococcus neoformans.

“…fluconazole) interfere with ergosterol biosynthesis by inhibiting the enzyme lanosterol 14-α-demethylase. Because ergosterol is a major constituent of the fungal membranes, its depletion results in growth inhibition (44). Since Vps45 was found to be associated with plasma and vacuolar membranes, and a mutant displayed defects in cell wall integrity, we tested the sensitivity of vps45 mutants to cell wall, antimalarial, and azole drugs.…”

DFT Study, POM Analyses and Molecular Docking of Novel Oxazaphosphinanes: Identification of Antifungal Pharmacophore Site

“…Computer-based molecular docking can facilitate the early stages of drug discovery through systematic prescreening of ligands (i.e., small molecules) for shape and energetic compatibility with a receptor (i.e., protein) prior to experimental evaluation [33][34][35]. Recently, small chemical ligands have been reported to inhibit cytochrome P450 sterol 14α-demethylase in a wide spectrum of fungal species [36][37][38]. To understand the mechanism of action and antifungal activity of our synthesized analogues, molecular docking studies were employed using the crystal structure of human cytochrome P450 2E1 that was picked from the Protein Data Bank (CYP2E1; pdb code: 3e4e) (http://www.rcsb.org/pdb).…”

Antifungal activity of immunosuppressants used alone or in combination with fluconazole

“…Azole antifungal agents are considered to be first‐line therapeutic drugs for fungal infections because of their effective antifungal activity and good safety profile (Hashemi et al . ; Nabili et al . ).…”

“…Azole antifungal agents are considered to be first-line therapeutic drugs for fungal infections because of their effective antifungal activity and good safety profile (Hashemi et al 2015;Nabili et al 2016). However, the long-term use of azoles has resulted in the emergence of resistant strains.…”