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 Mtb CM) 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 Mtb CM (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-iodophenols with appropriate terminal alkynes. A range of novel 3-(benzofuran-2-ylmethyl) 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 μM 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.