Synthesis, Reduction Potentials, and Antitubercular Activity of Ring A/B Analogues of the Bioreductive Drug (6<italic>S</italic>)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5<italic>H</italic>-imidazo[2,1-<italic>b</italic>][1,3]oxazine (PA-824)

The nitroimidazooxazine S-1 (PA-824) is a new class of bioreductive drug for tuberculosis. A series of related bicyclic nitroheterocycles was synthesized, designed to have a wide range of one-electron reduction potentials E(1) (from -570 to -338 mV, compared with -534 mV for S-1). The observed E(1) values closely correlated with the σm values of the heteroatom at the 4/8-position of the adjacent six-membered ring. Although the compounds spanned a range of E(1) values around that of S-1, only the nitroimidazothiazines showed significant antitubercular activity (at a similar level of potency), suggesting that E(1) is not the main driver of efficacy. Furthermore, there was a correlation between activity and the formation of imidazole ring-reduced products at the two-electron level, pointing to the potential importance of this reduction pathway, which is determined by the nature of the substituent at the 2-position of the 4-nitroimidazole ring.