1,2,3-Triazole analogs with bulky and conformationally rigid substructures: Synthesis and in vitro evaluation as DPP-4 inhibitors

Novel 1,2,3-triazole analogs with bulky and conformationally rigid azacyclic/azabicyclic amine and alcohol substructures at the C4 position were synthesized and evaluated for their inhibitory activities against human dipeptidyl peptidase-4 enzyme. The synthesized 1,2,3-triazole analogs (2a-2f) exhibited moderate in vitro hDPP-4 inhibitory activities (0.32-> 2.0 mu M) in comparison to the analog with the C4 tert-Bu group (0.24 mu M). However, the reduced bioactivity of the 1,2,3-triazole analogs with bulky and conformationally rigid substructures might be attributed to the lower-than-anticipated van der Waals interactions of the introduced heterocycles. Another plausible explanation for the reduced activity could be due to the role of two other factors (pi-pi interaction and H-bonding) in influencing the interaction of the analogs with the key amino residues in the pocket of the enzyme. Further research is encouraged to explore the role of these factors in deciding the enzyme-inhibiting activities of the C4 substituted 1,2,3-triazole analogs.