title: Structure-activity relationships of antitubercular nitroimidazoles. 3. Exploration of the linker and lipophilic tail of ((s)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)amine (6-amino PA-824).
abstract: The (S)-2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine named PA-824 (1) has demonstrated antitubercular activity in vitro and in animal models and is currently in clinical trials. We synthesized derivatives at three positions of the 4-(trifluoromethoxy)benzylamino tail, and these were tested for whole-cell activity against both replicating and nonreplicating Mycobacterium tuberculosis (Mtb). In addition, we determined their kinetic parameters as substrates of the deazaflavin-dependent nitroreductase (Ddn) from Mtb that reductively activates these pro-drugs. These studies yielded multiple compounds with 40 nM aerobic whole cell activity and 1.6 μM anaerobic whole cell activity: 10-fold improvements over both characteristics from the parent molecule. Some of these compounds exhibited enhanced solubility with acceptable stability to microsomal and in vivo metabolism. Analysis of the conformational preferences of these analogues using quantum chemistry suggests a preference for a pseudoequatorial orientation of the linker and lipophilic tail.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, Singapore, 138670.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cherian
authors.forename: Inhee
authors.initials: I
authors.lastname: Choi
authors.forename: Amit
authors.initials: A
authors.lastname: Nayyar
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.forename: Tathagata
authors.initials: T
authors.lastname: Mukherjee
authors.forename: Yong Sok
authors.initials: YS
authors.lastname: Lee
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.forename: Young Hwan
authors.initials: YH
authors.lastname: Ha
authors.forename: Michael
authors.initials: M
authors.lastname: Goodwin
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Pornwaratt
authors.initials: P
authors.lastname: Niyomrattanakit
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
authors.forename: Sindhu
authors.initials: S
authors.lastname: Ravindran
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007700:Kinetics; D008657:Metabolic Clearance Rate; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009593:Nitroimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009601:Nitroreductases / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009593:Nitroimidazoles; D011355:Prodrugs; C410767:pretomanid; D009601:Nitroreductases