Design, synthesis and biological evaluation of isatin-benzotriazole hybrids as new class of anti- Candida agents

A novel series of triazole tethered isatin-benzotriazole hybrids has been designed as potential antifun-gal agents against Candida strains. Hybrid molecules were synthesised via click chemistry approach and characterized by NMR and Mass spectroscopic techniques. Among the synthesized hybrids, AS14 showed most potent activity against fluconazole resistant Candida albicans with minimum inhibitory concentra-tion (MIC) and minimum fungicidal concentration (MFC) values of 3.9 and 7.8 mu M respectively. Structure -activity relationship studies revealed that fluoro (F) substitution on 5th position of isatin nucleus and four carbon distance between isatin and triazole moiety is most tolerable for inhibitory potential of the struc-ture against Candida albicans. AS14 was also capable to inhibit biofilm formation and ergosterol synthesis in Candida albicans. Molecular docking studies revealed the favourable binding pattern of AS14 with sterol 14 alpha-demethylase enzyme (CYP51) of Candida albicans. Furthermore, molecular dynamic studies suggested the stability of enzyme-hybrid complex. Overall study suggested that hybrid AS14 can act as an effective hit lead for further development of potent and safer antifungal agents for tackling Candida infections.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

A series of triazole tethered isatin-benzotriazole hybrids were designed and synthesized as potential antifungal agents against Candida strains. Among the synthesized hybrids, AS14 showed the most potent activity against fluconazole resistant Candida albicans. Structure-activity relationship studies revealed the optimal substitutions for inhibitory potential of the structure against Candida albicans. AS14 was also able to inhibit biofilm formation and ergosterol synthesis in Candida albicans, and molecular docking and dynamic studies supported its effectiveness and stability. Overall, AS14 can serve as a promising lead for the development of potent and safer antifungal agents for Candida infections.