Indole-bearing azoles as highly promising antifungals with in vitro efficacy against clinical isolates of Candida
Journal of Molecular Structure, cilt.1381, 2027 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1381
- Basım Tarihi: 2027
- Doi Numarası: 10.1016/j.molstruc.2026.147477
- Dergi Adı: Journal of Molecular Structure
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Anahtar Kelimeler: Azole, Candida, Clinical isolate, CYP3A4, CYP51, Cytotoxicity, Indole, Molecular modelling, X-ray diffraction
- Hacettepe Üniversitesi Adresli: Evet
Özet
Systemic and invasive candidiasis is a growing threat with increasing drug resistance and worsening global health condition due to pandemics like COVID. Antifungal chemotherapy is an under-researched field with very few new approvals over the past decades. Azoles have been a promising class in this respect, albeit with problems of growing resistance, drug-drug interactions, toxicity and adverse effects. Herein we report a group of new azoles and the promise of indole substituent for potent antifungal effects and favourable properties. The title compounds were tested against a collection of reference strains and clinical isolates (n = 100) of Candida spp., some of which proved effective against azole non-susceptible species such as Candida glabrata, Candida krusei, Candida guilliermondii, and Candida inconspicua with minimum inhibitor concentrations (MICs) much lower than those of fluconazole. The compounds were highly effective against Candida albicans and Candida parapsilosis isolates with acquired fluconazole resistance obtaining MICs as low as 0.008 mg/l. Cytotoxicity studies revealed negligible toxicity, while inhibitory effects on human CYP3A4, a major hotspot for drug-drug interactions, were found very low for 6l, a 1,2,4-triazole derivative. We tried to provide valuable insights into action mechanism of the compounds as fungal CYP51 inhibitors and significance of indole at molecular level using molecular modelling and virtual screening. Varying susceptibility among the Candida species towards the title compounds was investigated by the help of homology modelling. The study highlights new indole-bearing azoles as a potential weapon in the fight against azole-resistant Candida infections with druglikeness, cellular safety, and ability to avoid drug-drug interactions.