title: Metabolism-directed structure optimization of benzimidazole-based Francisella tularensis enoyl-reductase (FabI) inhibitors.
abstract: 1. FabI is a potential antibiotic target against Francisella tularensis, which has been classified as a Category A biowarfare agent of high risk to public health. Our previous work demonstrated that N-benzyl benzimidazole compounds possess promising FabI inhibitory activity, but their druggability properties, including metabolic stability, are unknown. 2. The objective of this study was to characterize structure-metabolism relationships of a series of N-benzyl benzimidazole compounds to guide chemical optimization for better metabolic stability. To this end, metabolic stability data were obtained for 22 initial lead compounds using mouse hepatic microsomes. 3. Metabolic hotspots on the benzimidazole core structure as well as the benzyl ring were identified and verified by metabolite identification studies of four model compounds. Interestingly, the proposed structure-metabolism relationships did not apply to nine newly synthesized cyclopentane or oxacyclopentane derivatives of N-benzyl benzimidazole. 4. Subsequently, in silico quantitative structure-property relationship models were developed. Four molecular descriptors representing molecular polarity/polarisability, symmetry and size were identified to best explain variability in metabolic stability of different compounds. Multi-linear and non-linear regression models based on the selected molecular descriptors were developed and validated. 5. The structure-metabolism relationships for N-benzyl benzimidazole compounds should help optimization of N-benzyl benzimidazole compounds for better pharmacokinetic behavior.
authors.affiliation: Department of Pharmacy Practice, Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago , Chicago, IL , USA .
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Shahila
authors.initials: S
authors.lastname: Mehboob
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Song
authors.forename: Teuta
authors.initials: T
authors.lastname: Boci
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Hyunyoung
authors.initials: H
authors.lastname: Jeong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005604:Francisella tularensis / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D001798:Blood Proteins; D004791:Enzyme Inhibitors; C031000:benzimidazole; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)