Synthesis of 1,2,3-Triazole Analogs of Linagliptin as Novel DPP-4 Inhibitors: DFT, Molecular Docking Approach

The synthesis of some novel 1,2,3-triazole-based linagliptin derivatives from the CuI catalyzed 1,3-dipolar cycloaddition reaction between N-propargyl purines and several aryl azides as described herein. All these new compounds were further evaluated for their in vitro dipeptidyl peptidase-4 (DPP-4) activity and the compounds 8-bromo-1,3-dimethyl-7-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-purine-2,6(3H,7H)-dione, 7-(but-2-yn-1-yl)-1,3-dimethyl-8-(4-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl) piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione and 7-(but-2-yn-1-yl)-8-(4-((1-(3,5-dichloro phenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione have shown good inhibitory activity against DPP-4. Molecular docking studies were performed for the promising compounds for their binding interactions with the receptor dipeptidyl peptidase IV (PDB ID-3G0B). The most potent compound was deliberated optimal structure, and data were calculated using the density functional theory (DFT) B3LYP method on a 6-311++G (d,p) basis set. The structural parameters were derived from geometry optimization. The HOMO and LUMO energies are calculated for the molecule.