title: Structure-activity relationships of antitubercular nitroimidazoles. 1. Structural features associated with aerobic and anaerobic activities of 4- and 5-nitroimidazoles.
abstract: The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.forename: Sejal
authors.initials: S
authors.lastname: Patel
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
mesh_terms: D000332:Aerobiosis; D000693:Anaerobiosis; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009601:Nitroreductases / Q000235:genetics; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D010078:Oxazines; D009601:Nitroreductases