Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound's pharmacology and provide guidelines for further lead optimization.

Automated summary

Twenty novel 2-substituted quinoline-4-carboxylic acids with amide moiety were designed and synthesized, and screened as potential hDHODH inhibitors. The compound 5j, with a chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. Molecular docking analysis of 5j on hDHODH provided insights into its pharmacology and guidance for further lead optimization.