Pyridylethanol(phenylethyl)amines are non-azole, highly selective Candida albicans sterol 14α-demethylase inhibitors.

Abstract

Sterol 14α-demethylase (CYP51) is the main drug target for the treatment of fungal infections. The worldwide increase in the incidence of opportunistic fungal infections and the emerging resistance to available azole-based antifungal drugs, raise the need to develop structurally distinct and selective fungal CYP51 inhibitors. In this work we have, for the first time, investigated the binding of pyridylethanol(phenylethyl)amines to any fungal CYP51. The comparison of the binding to Candida albicans and human CYP51 studied by spectroscopic and modeling methods revealed moieties decisive for selectivity and potency and resulted in the development of highly selective derivatives with significantly increased inhibitory potency. The structure-based insight into the selectivity requirements of this new chemical class of fungal CYP51 inhibitors, their unique binding properties and the low molecular weight of lead derivatives offer novel directions for the targeted development of antifungal clinical candidates.

• Authors: Iza Ogris, Urška Zelenko, Izidor Sosič, Martina Gobec, Cene Skubic, Marija Ivanov, Marina Soković, Darko Kocjan, Damjana Rozman, Simona Golič Grdadolnik
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 106 Pg. 104472 (01 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 33261849 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antifungal Agents
• Enzyme Inhibitors
• Sterol 14-Demethylase

Topics

• Antifungal Agents (chemical synthesis, chemistry, pharmacology)
• Candida albicans (drug effects, enzymology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Microbial Sensitivity Tests
• Molecular Structure
• Sterol 14-Demethylase (metabolism)
• Structure-Activity Relationship