Design and Synthesis of Pyrano[3,2-]indolones Showing Antimycobacterial Activity.

Latent infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their activity against strains H37Rv and streptomycin-starved 18b (SS18b), representing models for replicating and nonreplicating mycobacteria, respectively. Compound exhibited good activity with MIC values of 0.3 and 0.4 μg/mL against H37Rv and SS18b, respectively, as well as low toxicity, acceptable intracellular activity, and satisfactory metabolic stability and was selected as the lead compound for further studies. An analysis of -resistant mutants disclosed a cross-resistance with pretomanid and altered relative amounts of different forms of cofactor F in these strains. Complementation experiments showed that F-dependent glucose-6-phosphate dehydrogenase and the synthesis of mature F were important for activity. Overall these studies revealed to be a prodrug that is activated by an unknown F-dependent enzyme in mycobacteria.