title: Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).
abstract: Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (∼2- to 4-fold) potencies against replicating  Mycobacterium tuberculosis  but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute  M. tuberculosis  infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Adrian
authors.initials: A
authors.lastname: Blaser
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Sutherland
authors.forename: Iveta
authors.initials: I
authors.lastname: Kmentova
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Thompson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000208:Acute Disease; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002908:Chronic Disease; D004285:Dogs; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy; D014508:Urea / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C570912:2-nitro-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazin-6-yl 4-(4-(trifluoromethoxy)phenyl)piperazine-1-carboxylate; D000577:Amides; D000995:Antitubercular Agents; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002219:Carbamates; D009593:Nitroimidazoles; D010879:Piperazines; C410767:pretomanid; D014508:Urea