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)

Adrian Blaser; Brian D Palmer; Hamish S Sutherland; Iveta Kmentova; Scott G Franzblau; Baojie Wan; Yuehong Wang; Zhenkun Ma; Andrew M Thompson; William A Denny

doi:10.1021/jm2012276

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)

J Med Chem. 2012 Jan 12;55(1):312-26. doi: 10.1021/jm2012276. Epub 2011 Dec 29.

Authors

Adrian Blaser¹, Brian D Palmer, Hamish S Sutherland, Iveta Kmentova, Scott G Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, Andrew M Thompson, William A Denny

Affiliation

¹ Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

PMID: 22148391
DOI: 10.1021/jm2012276

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Disease
Amides / chemical synthesis*
Amides / pharmacokinetics
Amides / pharmacology
Animals
Antitubercular Agents / chemical synthesis*
Antitubercular Agents / pharmacokinetics
Antitubercular Agents / pharmacology
Biological Availability
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / pharmacokinetics
Biphenyl Compounds / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Carbamates / chemical synthesis*
Carbamates / pharmacokinetics
Carbamates / pharmacology
Chronic Disease
Dogs
Humans
Mice
Microbial Sensitivity Tests
Microsomes, Liver / metabolism
Models, Molecular
Mycobacterium tuberculosis / drug effects
Nitroimidazoles / chemical synthesis*
Nitroimidazoles / pharmacokinetics
Nitroimidazoles / pharmacology
Piperazines / chemical synthesis*
Piperazines / pharmacokinetics
Piperazines / pharmacology
Rats
Solubility
Stereoisomerism
Structure-Activity Relationship
Tuberculosis, Pulmonary / drug therapy
Urea / chemical synthesis*
Urea / pharmacokinetics
Urea / pharmacology

Substances

2-nitro-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazin-6-yl 4-(4-(trifluoromethoxy)phenyl)piperazine-1-carboxylate
Amides
Antitubercular Agents
Biphenyl Compounds
Bridged Bicyclo Compounds, Heterocyclic
Carbamates
Nitroimidazoles
Piperazines
pretomanid
Urea