Novel Triazoles with Potent and Broad-Spectrum Antifungal Activity In Vitro and In Vivo

Abstract

Triazoles have demonstrated significant efficacy in the treatment of fungal infections. However, increasing drug resistance is a growing concern that negatively impacts their effectiveness. By designing a well-crafted side chain, triazoles can be endowed with advantages, like higher potency and the ability to overcome drug resistance. This highlights the diverse interactions between side chains and CYP51. To explore novel triazole antifungal agents, we synthesized three series of fluconazole-core compounds and focused on optimizing the chain based on molecule docking and in vitro results. The most potent S-F24 exhibited excellent broad-spectrum antifungal activity that was better or comparable to clinically used azoles. S-F24 maintained its potency even against multi-resistant Candida albicans. Additionally, S-F24 displayed a good safety profile with high selectivity, low hemolytic effects, and low tendency to induce resistance. Our findings collectively demonstrated that there was still a high potential for side-chain modification in the development of novel azoles.

Evaluation of the antidermatophytic activity of potassium salts of N-acylhydrazinecarbodithioates and their aminotriazole-thione derivatives

“…For the triazole group of 2d , in turn, three hydrogen bonds were predicted between its amino group at the N4 position and the carbonyl group of Tyr-505, the N2 nitrogen atom and the carbonyl group of Pro-375, as well as between the N1 nitrogen atom and the amino group of conserved residue (His-377) in all CYP51 enzymes from the Candida genera 36 , In contrast to long-tailed native inhibitor VT1161, neither coordination bond with the prosthetic heme iron through the triazole ring of 2d nor its close contacts with the heme-binding core region were recorded. Additionally, no close interactions of 2d with Tyr-132, recognized as a crucial residue to the antifungal ability 38 were observed. Thus, we can conclude that although short-tailed 2d can inhibit CYP51 activity by competing with the sterol substrate for the space within the enzyme-active site, it cannot affect the iron potential to be reduced 36 .…”

Synthesis and Biological Evaluation of a Series of New Hybrid Amide Derivatives of Triazole and Thiazolidine-2,4-dione

“…Thiazolidine-substituted carboxylic acids 11-15 (Scheme 2) and their 5-arylidene derivatives 20-22 were obtained from thiazolidine-2,4-dione (5) by reproduction of the methods described in the literature [25][26][27] and presented in the Supporting Information. 20 , L-310 16 , L-163 16 .…”

“…For the next steps, the salts of 4a and 4b or their freebases are equally suitable. 20 , L-310 16 , L-163 16 .…”

“…Microbiological evaluation of all the obtained derivatives of thiazolidine and triazole was carried out on strains of pathogenic yeast-like fungi Candida albicans, C. nonalbicans, C. auris, filamentous fungi Aspergillus spp., dermatophytes T. rubrum, M. canis, and Rhizopus spp. 20 , L-310 16 , L-163 16 .…”

Design, synthesis and evaluation of 2-phenylpyrimidine derivatives as novel antifungal agents targeting CYP51

“…Human fungal infections could be divided into common and slight superficial fungal infections (SFIs) and life-threatening invasive fungal infections (IFIs). 1–3 As modern medicine advances, many incurable SFIs in the past can be treated by drugs, but more and more people especially patients with weakened immune systems can become vulnerable to invasion by IFIs. 4,5 In patients with COVID-19, fungal pathogens have been discovered to cause severe secondary infections, which has aroused our concern about IFIs.…”