Metabolism‐Directed Structure Optimization of Benzimidazole‐Based F. Tularensis Enoyl‐Reductase (FabI) Inhibitors
Yan‐Yan Zhang, Michael E. Johnson, Arun Kumar Ghosh, Hyunyoung Jeong · The FASEB Journal · 2013
FabI is an attractive antibiotic target against F. Tularensis , a Category A biowarfare agent of high risk to public health. Our previous study identified a novel class of benzimidazole analogs possessing excellent FabI inhibitory activity but unknown metabolic stability. The objective of this study was to characterize structure‐metabolism relationships (SMR) for this series to guide chemical modification. To this end, hepatic microsomal stability and bioactivity data were obtained for 22 lead compounds. Methyl, methoxy, or methylenedioxy substitution at the core structure was found unfavorable to the metabolic stability. Metabolite identification studies on 4 model compounds revealed hydroxylation of the benzimidazole ring as the major metabolic route. Introduction of methyl groups on this moiety provided additional metabolic soft spots. Cyclic modification strategy was then proposed, and 9 cyclopentane and oxacyclopentane derivatives were newly synthesized, which showed 4–13‐fold increases in t1/2 without impaired bioactivity. Subsequently, quantitative SMR models were successfully constructed using genetic algorithm variable selection, multi‐linear regression and artificial neural network techniques. Collectively, SMR for the FabI inhibitors were systematically analyzed, and the results should help product optimization for optimal pharmacokinetic properties.