Benzoic acid derivatives with improved antifungal activity: Design, synthesis, structure-activity relationship (SAR) and CYP53 docking studies

Sabina Berne; Lidija Kovačič; Matej Sova; Nada Kraševec; Stanislav Gobec; Igor Križaj; Radovan Komel

doi:10.1016/j.bmc.2015.06.042

Benzoic acid derivatives with improved antifungal activity: Design, synthesis, structure-activity relationship (SAR) and CYP53 docking studies

Bioorg Med Chem. 2015 Aug 1;23(15):4264-4276. doi: 10.1016/j.bmc.2015.06.042. Epub 2015 Jun 25.

Authors

Sabina Berne¹, Lidija Kovačič², Matej Sova³, Nada Kraševec⁴, Stanislav Gobec³, Igor Križaj⁵, Radovan Komel⁶

Affiliations

¹ Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia. Electronic address: sabina.berne@mf.uni-lj.si.
² Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; UCD Conway Institute, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
³ Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
⁴ National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
⁵ Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.
⁶ Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia. Electronic address: radovan.komel@mf.uni-lj.si.

PMID: 26154240
DOI: 10.1016/j.bmc.2015.06.042

Abstract

Previously, we identified CYP53 as a fungal-specific target of natural phenolic antifungal compounds and discovered several inhibitors with antifungal properties. In this study, we performed similarity-based virtual screening and synthesis to obtain benzoic acid-derived compounds and assessed their antifungal activity against Cochliobolus lunatus, Aspergillus niger and Pleurotus ostreatus. In addition, we generated structural models of CYP53 enzyme and used them in docking trials with 40 selected compounds. Finally, we explored CYP53-ligand interactions and identified structural elements conferring increased antifungal activity to facilitate the development of potential new antifungal agents that specifically target CYP53 enzymes of animal and plant pathogenic fungi.

Keywords: Antifungal activity; Benzoic acid; CYP53; Cytochrome P450; Molecular docking; Molecular modeling; SAR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry*
Antifungal Agents / pharmacology*
Ascomycota / drug effects
Aspergillus niger / drug effects
Benzoic Acid / chemistry*
Cytochromes / chemistry*
Cytochromes / metabolism
Drug Design
Drug Evaluation, Preclinical / methods
Fungal Proteins / chemistry
Fungal Proteins / metabolism
Magnetic Resonance Spectroscopy
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Targeted Therapy / methods
Pleurotus / drug effects
Protein Conformation
Structure-Activity Relationship*

Substances

Antifungal Agents
Cytochromes
Fungal Proteins
Benzoic Acid