ZHANG JZ, WATKINS WJ, LEE VJ, MCMILLEN W, BELEJ P, MATHIAS K, BLAIS J, CHO D, GRIFFITH D, DUDLEY MN, OHTA T, NAKAYAMA K, ISHIDA Y; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. F-342.
Microcide Pharmaceuticals, Inc., Mountain View, CA
MC-278,537, a symmetrical bis(2-(aminoalkyl)benzimidazole), is a new broad-spectrum efflux pump inhibitor discovered by high-throughput screening. Exploratory medicinal chemistry efforts were initiated around the lead to increase potentiation activity, and to reduce cytotoxicity and acute toxicity. Following truncation of the lead and examination of various heterocycles, the benzimidazole analogs were the least toxic. The potentiation of levofloxacin in vitro was improved by introduction of a lipophilic moiety at either 1- or 5-position of the benzimidazole scaffold, and a second amine moiety at the 2-position. Structure-Activity Relationship (SAR) studies indicated that two basic amines and a lipophilic group, on the benzimidazole scaffold, were required for potentiation activity. These studies resulted in the discovery of MC-04,112, an agent that gives 8-fold potentiation of levofloxacin in wild-type P. aeruginosa at 10 microg/ml. The TC[50] in an in vitro K-562 mammalian cytotoxicity assay is 275 micro-M, and the minimum lethal dose in mice is 70 mg/kg (i.v. bolus). Comparison of the topology and SAR of this series with that of other broad-spectrum EPIs (see accompanying posters) suggests that the pharmacophore in these cases is similar.
Publication Types:
Keywords:
- Animals
- Benzimidazoles
- In Vitro
- Mice
- Motor Activity
- Ofloxacin
- Pseudomonas aeruginosa
- Structure-Activity Relationship
- antagonists & inhibitors
- benzimidazole
- classification
Other ID:
UI: 102269868
From Meeting Abstracts