title: Structure-based design of novel benzoxazinorifamycins with potent binding affinity to wild-type and rifampin-resistant mutant Mycobacterium tuberculosis RNA polymerases.
abstract: By utilization of three-dimensional structure information of rifamycins bound to RNA polymerase (RNAP) and the human pregnane X receptor (hPXR), representative examples (2b-d) of a novel subclass of benzoxazinorifamycins have been synthesized. Relative to rifalazil (2a), these analogues generally display superior affinity toward wild-type and Rif-resistant mutants of the Mycobacterium tuberculosis RNAP but lowered antitubercular activity in cell culture under both aerobic and anaerobic conditions. Lowered affinity toward hPXR for some of the analogues is also observed, suggesting a potential for reduced Cyp450 induction activity. Mouse and human microsomal studies of analogue 2b show it to have excellent metabolic stability. Mouse pharmacokinetics in plasma and lung show accumulation of 2b but with a half-life suggesting nonoptimal pharmacokinetics. These studies demonstrate proof of principle for this subclass of rifamycins and support further expansion of structure-activity relationships (SARs) toward uncovering analogues with development potential.
authors.affiliation: Interdepartmental Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Sumandeep K
authors.initials: SK
authors.lastname: Gill
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kirchhoff
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.forename: Anjanette J
authors.initials: AJ
authors.lastname: Turbiak
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Kuan-Wei
authors.initials: KW
authors.lastname: Peng
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: George A
authors.initials: GA
authors.lastname: Garcia
authors.forename: H D Hollis
authors.initials: HD
authors.lastname: Showalter
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000138:chemical synthesis / Q000493:pharmacokinetics; D048588:Benzoxazines / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics; D012293:Rifampin / Q000494:pharmacology; D012294:Rifamycins / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000904:Antibiotics, Antitubercular; D048588:Benzoxazines; D012294:Rifamycins; D012321:DNA-Directed RNA Polymerases; D012293:Rifampin