Blaser, A; Palmer, BD; Sutherland, HS; Kmentova, I; Franzblau, SG; Wan, B; Wang, Y; Ma, Z; Thompson, AM; Denny, WA; ,
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.
1 (3 bromophenyl) 3 [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl]urea; 1 [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl 3 [4' (trifluoromethoxy)biphenyl 3 yl]urea; 1 [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl] 3 [4 (trifluoromethoxy)phenyl]thiourea; 1 [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl] 3 [4 (trifluoromethoxy)phenyl]urea; 2 (4 bromophenyl) n [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl]acetamide; 2 [[2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl]amino] 1 [4 (trifluoromethoxy)phenyl]ethanone; 2 nitro 6 [[2 (trifluoromethoxy)benzyl]oxy] 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazine; 2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl 4 [4 (trifluoromethoxy)phenyl]acetamide; 2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl 4 [4 (trifluoromethoxy)phenyl]carbamate; 2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl 4 [4 (trifluoromethoxy)phenyl]piperazine 1 carboxylate; 2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl(3 bromophenyl]carbamate; 2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl[4' trifluoromethyl)biphenyl 3 yl]carbamate; 4 (trifluoromethoxy)phenyl[2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl]carbamate; 4 iodobenzyl[2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl]carbamate; 6,7 dihydro 2 nitro 6 (4 trifluoromethoxybenzyloxy) 5h imidazo[2,1 b][1,3]oxazine; [4' (trifluoromethyl)biphenyl 4 yl]methyl[2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl]carbamate; amide; carbamic acid derivative; delamanid; n [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl] 2 (trifluoromethoxy)benzamide; n [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl] 2 (trifluoromethoxy)benzenesulfonamide; n [2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl] 2 [4 (trifluoromethyl)biphenyl 4 yl]acetamide; n methyl n[2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl] 2 (trifluoromethoxy)benzamide; n methyl n[2 nitro 6,7 dihydro 5h imidazo[2,1 b][1,3]oxazin 6 yl] 2 (trifluoromethoxy)benzenesulfonamide; unclassified drug; urea; aerobic metabolism; animal experiment; animal model; article; drug bioavailability; drug efficacy; drug potency; in vivo study; lipophilicity; male; mouse; Mycobacterium bovis; Mycobacterium tuberculosis; nonhuman; rat; single drug dose; solubility; structure activity relation; tuberculosis; Acute Disease; Amides; Animals; Antitubercular Agents; Bicyclo Compounds, Heterocyclic; Biological Availability; Biphenyl Compounds; Carbamates; Chronic Disease; Dogs; Humans; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Models, Molecular; Mycobacterium tuberculosis; Nitroimidazoles; Piperazines; Rats; Solubility; Stereoisomerism; Structure-Activity Relationship; Tuberculosis, Pulmonary; Urea