LAUSR

A series of 1H‐1,2,3‐triazole−4H‐chromene−D‐glucose hybrid compounds 7a–w were synthesized using click chemistry of 2‐amino‐7‐propargyloxy‐4H‐chromene‐3‐carbonitriles 5a–w. CuNPs@montmorillonite was used as a catalyst in the presence of DIPEA as an additive for this chemistry. All synthesized 1H‐1,2,3‐triazoles were examined for in vitro inhibition against Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB). Nine 1H‐1,2,3‐triazoles, including 7c–e, 7h, 7i, and 7r–t, displayed remarkable inhibitory activity against MtbPtpB with IC50 < 10 μM; compound 7t exhibited the most potent inhibition in vitro with an IC50 value of 0.61 μM. Kinetic studies of the three most active compounds, 7c,h,t, showed their competitive inhibition toward the MtbPtpB enzyme. Induced‐fit docking and MM‐GBSA studies on the enzyme (PDB: 2OZ5) revealed that the most active compound 7t was more effective against MtbPtpB. Residues Arg64, Arg136, Ash165, Arg166, and Arg63 in the binding pocket were identified as potential ligand‐binding hot‐spot residues for ligand 7t. The binding free energy calculation by the MM‐GBSA approach for ligand 7t indicated that Coulomb, lipophilic, and van der Waals energy terms are major contributors to the inhibitor binding. Furthermore, the stability of the ligand‐protein complex and the structural insights into the mode of binding were confirmed by 300‐ns molecular dynamics simulation of 7t/2OZ5.