High-Throughput-Screening-Based Identification and Structure–Activity Relationship Characterization Defined (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole as a Highly Antimycotic Agent Nontoxic to Cell Lines

• Published in: Journal of medicinal chemistry Vol. 54; no. 19; pp. 6993 - 6997
• Main Authors: Bauer, Jörg, Kinast, Stephan, Burger-Kentischer, Anke, Finkelmeier, Doris, Kleymann, Gerald, Rayyan, Walid Abu, Schröppel, Klaus, Singh, Anurag, Jung, Günther, Wiesmüller, Karl-Heinz, Rupp, Steffen, Eickhoff, Holger
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2011; Amer Chemical Soc
• Subjects: Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Antimitotic Agents - chemical synthesis; Antimitotic Agents - pharmacology; Antimitotic Agents - toxicity; Benzimidazoles - chemical synthesis; Benzimidazoles - pharmacology; Benzimidazoles - toxicity; Candida - drug effects; Candida - genetics; Cell Line, Tumor; Chemistry, Medicinal; Drug Screening Assays, Antitumor; High-Throughput Screening Assays; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Imidazoles - toxicity; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Mycology - methods; Pharmacology & Pharmacy; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Transcription, Genetic - drug effects; ANTIFUNGAL AGENTS; CANDIDA
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200571e

Novel nontoxic (S)-2-aminoalkylbenzimidazole derivatives were found to be effective against Candida spp. at low micromolar concentrations using high-throughput screening with infected HeLa cells. A collection of analogues defined the chemical groups relevant for activity. The most active compound was characterized by transcriptional analysis of the response of C. albicans Sc5314. (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole had a strong impact on membrane biosynthesis. Testing different clinically relevant pathogenic fungi showed the selectivity of the antimycotic activity against Candida species.