Executive Summary : | One of the greatest needs in global health is the development of new drugs against tuberculosis (TB) that shorten the duration of TB chemotherapy and are potent against drug resistant strains of Mycobacterium tuberculosis (Mtb). However, achieving this goal will require to identify a new compound with a novel mechanism of action. The recently approved bedaquiline (BDQ, Sirturo) exerts its antimycobacterial activity through shutdown of ATP production by inhibition of F-type ATP synthase clinically validates oxidative phosphorylation as a pharmacologic target in Mtb (figure 1) (Pym et al., 2016). Nevertheless, the successful advance of BDQ is overshadowed by the emergence of clinical resistance less than 3 years after its introduction to medical use (Bloemberg et al., 2015). The rapid emergence of resistance is most likely linked to the absence of potent companion drugs. The electron transport chain (ETC) responsible for oxidative phosphorylation in bacteria is present in the membrane. Type II NADH dehydrogenase (NADH II) being the component of complex-I of ETC, transport electrons to terminal oxidases (cytochrome aa3-type or cytochrome bd-type) and generate proton motive force required for synthesis of ATP (Vilcheze et al., 2018). Inhibition of NADH II will impair the electron movement and may result in the death of the bacteria due to the depletion of ATP. Also, NADH II is absent in the mammalian genome, thus making it a potential drug target. Recently, Harbut et al. screened 8,00,000 compounds and identified CBR-1825 (MIC 1.2 ?M, figure 2) as a potent NADH II inhibitor (Harbut et al., 2018). Murgesan et al., replaced the six-member saturated ring in CBR 1825 with phenyl ring resulted 2-mercaptoquinazolinone amides (CBR-5992, figure 2) with MIC values 0.67 ?M. On further exploring the substrate scope, around cyclohexyl amide side chain, resulted decrease in activity (Murgesan et al., 2018). Most of the SAR studies were performed around the amide side chain because substituted 2-mercaptoquinazolinones are rarely available and difficult to synthesize. Unlike many antibacterial agents commonly used to treat mycobacterial infections, benzothiazole amides demonstrated bactericidal effects against Mtb (Groote et al. 2018, Mir et al. 2014, Landge et al. 2015, Venugopala et al. 2019). Viewed in this context, we replaced 2-mercaptoquinazolinone in CBR 5992 with 2-mercaptobenzothiazoles and generated a small library of 14 compounds. Fortunately, we have identified few compounds deplete ATP better than CBR 5992. In current project proposal, we want to expand the library of 2-mercaptobenzothiazole amides with two goals in mind- first, to assess a potential antitubercular compound with bactericidal activity and, second, to determine if it is associated with NADH II inhibition. Also, we believe that a drug combination containing NADH II inhibitor with other ETC inhibitors will be the cornerstone of a sterilizing drug regimen for tuberculosis. |