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

Objectives: To synthesize new anti mycobacterial and antifungal drugs that act by binding to sterol 14 alpha-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-14 alpha-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.