Concise route to stereoselective chlorobenzene-based spiropyrrolidine oxindoles for pursuit as antitubercular agents

A chemoselective chlorination of nitroolefin was accomplished, and the resulting monochlorinated nitroolefin underwent [3+2]-cycloadditions with in-situ generated azomethine-ylide to afford spiro pyrrolidine-oxindoles. All the compounds were tested against exponentially growing Mycobacterium tuberculosis H37Ra (Mtb-Ra) cells. Two of the compounds exhibited 90% inhibition at 3.125 µM and 6.25 µM concentrations, respectively. The ex vivo activity assay in macrophage J774A.1 cell line showed one log Colony Forming Unit (CFU) reduction for both compounds after 24 h and approximately 2 log reduction after 48 h, suggesting almost 99% killing of Mtb-Ra after 48 h of exposure in macrophages. Although the cytotoxicity studies with both compounds showed low toxicity at MIC values for both compounds, given the efficient killing of Mtb-Ra in macrophages, the present group of compounds is interesting, and further work is in progress to reduce the toxicity of these compounds for further activity studies.

Graphical abstract

SYNOPSIS. Chemoselective chlorination of nitroolefins using iodobenzene dichloride (IBDC) was carried out to obtain monochlorinated nitroolefins. This was further demonstrated for [3+2]-cycloadditions with azomethine ylide and isatin to synthesize spiropyrrolidine oxindoles. This work also presents that two of the synthesized compounds was able to exhibit good activity against Mycobacterium tuberculosis H37Ra (Mtb-Ra) cells.