Synthesis and Structure−Activity Relationships of Aza- and Diazabiphenyl 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 heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.

In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

“…A previous experiment conducted using the same preclinical model of TB as was used in the present work demonstrated that the efficacy of TBA-354 is superior to that of Pa when administered at the same dose and similar to that of delamanid against acute and chronic murine TB (23). Using the same low-dose aerosol infection model, these findings were extended here to demonstrate significant dose-and time-dependent bactericidal activity of TBA-354 against chronic murine TB.…”

“…Because of this, several independent medicinal chemistry programs have aimed to optimize these compounds further (8). Our own medicinal chemistry program, with the Auckland Cancer Society Research Center, identified TBA-354 as a particularly potent nitroimidazo-oxazine with ADME and PK characteristics suggesting suitability for once-daily oral dosing (23). The data we report herein confirm and extend these findings.…”

“…A facile explanation for the superior in vivo potency of TBA-354 over Pa is that, in addition to the lower MIC and MBC of TBA-354 compared to those of Pa, TBA-354 has a longer plasma half-life in mice than Pa and demonstrated a greater plasma AUC following oral dosing to mice at 40 mg/kg (23). The important PK/pharmacodynamic (PD) drivers of efficacy for Pa against murine TB are time/MIC, followed by AUC/MIC (13).…”

“…TBA-354 (compound 93 in reference 23) was identified as having particular promise, with lower MICs than Pa, stability in human and mouse liver microsomes, and good bioavailability in rats. Dosed for 3 weeks, 100 mg/kg TBA-354 showed efficacy (CFU reduction) superior to that of 100 mg/kg Pa against acute and chronic murine TB and at 30 mg/kg outperformed delamanid against chronic murine TB when dosed for 8 weeks (23).…”

Nitroimidazoles for the Treatment of TB: Past, Present and Future

“…Further structure–function relationship studies were carried out with biaryl analogs of PA-824 with the replacement of proximal, distal as well as both aryl groups with six-membered nitrogen-containing heterocycles [35]. This allowed the overall structure to be nearly linear and, hence, a better ft in the putative hydrophobic pocket of the enzyme [33].…”