Abstract
Ambitious milestones set by the World Health Organisation (WHO) to end the tuberculosis epidemic by 2030 currently appear out of reach, and there remains an urgent need to develop more effective novel therapies. While exploring dipicolinic acid derivatives as putative glutamate racemase inhibitors, we recently discovered 6-nitropicolinamides as promising antituberculosis agents. SAR studies on the non-cytotoxic N-[4-(trifluoromethoxy)benzyl] hit 20 (MIC90 1.4 μM) confirmed the importance of the 6-nitro group and amide NH; side chain extension enhanced potency but reduced aqueous solubility, and some analogues were rapidly metabolised. The best new candidate (77: MIC90 0.30 μM) was well tolerated in mice and provided an adequate pharmacokinetic profile, although a time-kill assay indicated largely bacteriostatic activity. An analysis of its effects on cell wall lipids and mycolic acids revealed changes consistent with inhibiting arabinogalactan biosynthesis, and further testing against mutant or overexpressing mycobacterial strains identified the enzyme target as decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1).