Design and synthesis of novel pyrazole-phenyl semicarbazone derivatives as potential α-glucosidase inhibitor: Kinetics and molecular dynamics simulation study

A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and saeened for in vitro alpha-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the aglucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast alpha-glucosidase inhibition (IC50 values in the range of 65.1-695.0 mu M) even much more potent than standard drug acarbose (IC50 = 750.0 mu M). Among them, compounds 8o displayed the most potent alpha-glucosidase inhibitory activity (IC50 = 65.1 +/- 0.3 mu M). Kinetic study of compound 8o revealed that it inhibited alpha-glucosidase in a competitive mode (Ki = 87.0 mu M). Limited SAR suggested that electronic properties of substitutions have little effect on inhibitory potential of compounds. Cytotoxic studies demonstrated that the active compounds (8o, 8k, 8p, 8l, 8i, and 8a) compounds are also non-cytotoxic. The binding modes of the most potent compounds 8o, 8k, 8p, 8l and 8i was studied through in silica docking studies. Molecular dynamic simulations have been performed in order to explain the dynamic behavior and structural changes of the systems by the calculation of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF). (C) 2020 Published by Elsevier B.V.

Automated summary

A series of novel pyrazole-phenyl semicarbazone derivatives were synthesized and tested for in vitro alpha-glucosidase inhibitory activity, with compound 8o showing the most potent inhibitory activity. Pharmacophore modification and molecular dynamic simulations supported the rational design and provided insights into the dynamic behavior and structural changes in the systems.