Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline derivatives

Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-c]quinolines, which are although considerably active (MIC 0.39–0.78 μg/mL) suffered from intense solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly esters of the “Lead” indeno[2,1-c]quinolines 1, 15 and 27 derivatives were synthesized and their prodrug nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold improved anti-TB activities, increased aqueous solubility and superior selectivity index over their respective parent compounds. MIC of these prodrugs was in the range of <0.20–6.0 μg/mL, and in general, no cytotoxicity was observed in VERO cells.

Graphical abstractProdrugs of lead “indeno[2,1-c]quinolines” are reported which have shown 2- to 4-fold improved anti-TB activity, increased aqueous solubility and superior selectivity index over their respective parent compounds.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► Synthesis and anti-TB activity of prodrugs of indeno[2,1-c]quinoline derivatives is described. ► Our previous potent antimycobacterial molecules, suffered from low solubility. ► Prodrug have enhanced aqueous solubility, lipophilicity and 2–4 fold increase in anti-TB activity. ► 33 molecules were found to possess in vitro anti-TB activity with MIC <0.20–6.0 μg/mL. ► Prodrugs also have good selectivity index (SI) and are non-toxic to normal human cell lines.