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

OBJECTIVES To synthesize new antimycobacterial and antifungal drugs that act by binding to sterol 14alpha-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) complexed 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 in the range 4-64 mg/L. Molecular modelling investigations showed that the active new compounds may interact at the active site of both the fungal and the mycobacterial cytochrome P450-dependent sterol-14alpha-demethylase and that the calculated binding free energy values are in agreement with the corresponding MIC values. CONCLUSIONS The combined experimental and computational approach can be helpful in targeted drug design, thus yielding valuable information for the synthesis and prediction of activity of a second generation of inhibitors.