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JAC Advance Access published online on May 18, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl182
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 23, 2006
Revised April 12, 2006
Accepted April 18, 2006

Original article

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

Elena Banfi 1 *, Giuditta Scialino 1, Daniele Zampieri 2, Maria Grazia Mamolo 2, Luciano Vio 2, Marco Ferrone 3, Maurizio Fermeglia 3, Maria Silvia Paneni 3, and Sabrina Pricl 3

1 Microbiology Laboratory, Department of Biomedical Sciences, University of Trieste, I-34127 Trieste, Italy
2 Department of Pharmaceutical Sciences, University of Trieste, I-34127 Trieste, Italy
3 Molecular Simulation Engineering (MOSE) Laboratory, Department of Chemical Engineering, University of Trieste, I-34127 Trieste, Italy

* To whom correspondence should be addressed.
Elena Banfi, E-mail: banfi{at}dsb.units.it


  Abstract

Objectives: To synthesize new antimycobacterial 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.

Keywords: antitubercular; molecular modelling; pyridinecarboxamidrazone-azole derivatives.
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