Design, synthesis and mechanistic study of new 1,2,4-triazole derivatives as antimicrobial agents

[Display omitted] •5-Amino-1,2,4-triazoles and 1,2,4-triazolo[1,5-a]pyrimidines were synthesized.•They were screened for antimicrobial activity and cytotoxicity at CO-ADD Australia.•Compounds 9, 13a, 13b showed best antifungal activities against candida albicans.•Compound 9 inhibited lansterol 14α-demethylase significantly (IC50 = 0.27 µM).•Molecular docking, in silico ADME and drug-likeness studies were performed. Novel 5-amino-1,2,4-triazole derivatives and their cyclized 1,2,4-triazolo[1,5-a]pyrimidine analogues were designed, synthesized and evaluated for their antimicrobial activities. They were tested against five bacterial strains (Methicillin Resistant S. aureus (MRSA), E. coli, K. pneumoniae, A. baumannii and P. aeruginosa) using ciprofloxacin as a positive control and against two fungal strains (C. albicans and C. neoformans) using fluconazole and amphotericin B as positive controls. Compounds 9, 13a and 13b showed high to moderate antifungal activities against candida albicans (MIC values = 4–32 µg/ml), with considerable safety profiles; where no cytotoxicity against human embryonic kidney or red blood cells were detected at concentrations up to 32 µg/mL. Furthermore, compound 9 showed significant inhibitory activity against lansterol 14α-demethylase (IC50 = 0.27 µM), compared to the reference drug fluconazole (IC50 = 0.25 µM). Molecular docking of compound 9 into the active site of the cytochrome P450 enzyme revealed comparable binding modes and docking scores to those of fluconazole. Finally, in silico ADME studies prediction and drug-like properties of these compounds revealed favorable oral bioavailability results.