Antifungal and antimycobacterial activity of new imidazole and triazole derivatives. A combined experimental and computational approach

To synthesize new antimycobacterial and antifungal drugs that act by binding to sterol 14α-demethylase (14DM) and to characterize the drug–target protein interactions using computer-based molecular simulations. Methods: Different series of imidazole and triazole derivatives having an azomethine linkage to pyridine 2-carboxamidrazone were designed and synthesized. Molecular dynamic simulations of the sterol 14DM (a mixed-function oxidase involved in sterol synthesis in eukaryotic and prokaryotic organisms) com- plexed with new azole derivatives have been performed to both qualify and quantify the protein–ligand interactions. MICs of the compounds were evaluated by reference assay and by the recently developed Microdilution Resazurin Assay (MRA). Results: Halogenated derivatives showed good activity, with an MIC90 of 1 mg/L against 33 Candida spp. clinical strains; most compounds also had inhibitory activity against Mycobacterium tuberculosis reference and clinical strains, with MICs