1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis

Abstract

New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-␤-D-ribose 2=-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is <1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis

“…5 Critically, these drugs, drug candidates, and screening hits have also been used to identify a number of new TB drug targets. These include the AtpE subunit of ATP synthase (the target of bedaquiline 6 ); the decaprenylphosphoryl-β- d -ribose 2-epimerase, DprE1 (the target of PBTZ169 7 and other pharmacophores 8 ); the trehalose monomycolate transporter, MmpL3 (the target of indolcarboxamides 9 and multiple other pharmacophores 10,11 ); QcrB, a component of the cytochrome bc 1 – aa 3 complex (the target of Q203 12 and other pharmacophores 13 ); DnaN, the target of griselimycin; 14 and FadD32, the target of diarylcoumarins. 15 By virtue of their novel mechanisms of action, drugs that are active against these targets have the potential to offer new therapeutic options for the treatment of DS- as well as DR-TB.…”

Newer Patents in Antimycobacterial Therapy

“…Clinical trials on this preclinical drug candidate would be initiated in 2015. Small molecule 1,4 azaindole and pyrazolopyridones cause noncovalent inhibition of DprE1 [111,112]. Nitroquinoxalines and 377790 triazole compounds also inhibit DprE1 enzyme [53].…”

New structural classes of antituberculosis agents

“…A detailed in vivo activity, solubility, and cytotoxicity profile of both analogues concluded 5 to be a promising candidate for clinical development. Compound 5 showed synergistic effects in vitro with two other classes of anti‐TB compounds PA824 and TMC207 (bedaquiline), and also exhibited in vivo synergy with TMC207 …”