title: Synthesis and structure-activity relationships of varied ether linker analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine (PA-824).
abstract: New analogues of antitubercular drug PA-824 were synthesized, featuring alternative side chain ether linkers of varying size and flexibility, seeking drug candidates with enhanced metabolic stability and high efficacy. Both α-methyl substitution and removal of the benzylic methylene were broadly tolerated in vitro, with a biaryl example of the latter class exhibiting an 8-fold better efficacy than the parent drug in a mouse model of acute  Mycobacterium tuberculosis  infection and negligible fragmentation to an alcohol metabolite in liver microsomes. Extended linkers (notably propenyloxy, propynyloxy, and pentynyloxy) provided greater potencies against replicating  M. tb  (monoaryl analogues), with propynyl ethers being most effective under anaerobic (nonreplicating) conditions (mono/biaryl analogues). For benzyloxybenzyl and biaryl derivatives, aerobic activity was maximal with the original (OCH(2)) linker. One propynyloxy-linked compound displayed an 89-fold higher efficacy than the parent drug in the acute model, and it was slightly superior to antitubercular drug OPC-67683 in a chronic infection model.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. am.thompson@auckland.ac.nz
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Thompson
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Sutherland
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.forename: Iveta
authors.initials: I
authors.lastname: Kmentova
authors.forename: Adrian
authors.initials: A
authors.lastname: Blaser
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: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000208:Acute Disease; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002908:Chronic Disease; D004987:Ethers; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D004987:Ethers; D009593:Nitroimidazoles; C410767:pretomanid