Pd/Cu-catalyzed access to novel 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinone derivatives: their in silico/in vitro evaluation as inhibitors of chorismate mutase (CM)

In view of the reported chorismate mutase (CM or MtbCM) inhibitory activities of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives the structurally similar 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinones were designed and evaluated in silico against CM. The docking of target molecules was performed at the interface site of MtbCM (PDB: 2FP2). All the best ranked molecules participated in a strong H-bonding with the ILE67 of the B chain at the backbone position in addition to several hydrophobic/van der Waals interactions with the hydrophobic residues. Based on encouraging docking results, the one-pot synthesis of newly designed benzofuran derivatives was carried out using tandem Pd/Cu-catalyzed Sonogashira cross-coupling followed by intramolecular cyclization of 2-odophenols with appropriate terminal alkynes. A range of novel 3-(benzofuran-2-yErnethyp substituted (pyrazolo/benzo)triazinone derivatives were prepared in high (>80%) yields. Three molecules i.e. 3h, 3i and 3m that participated in good interaction with CM in silico showed encouraging (64-65%) inhibition at 30 mu M in vitro. An SAR within this class of molecuLes suggested that the benzotriazinone series in general was better than the pyrazolotriazinone series. Based on molecular docking in silico, CM inhibition in vitro and computational ADME prediction the benzofuran derivatives 3i and 3m seemed to be of further medicinal interest in the context of discovery and development of new anti-tubercular agents.