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

• Published in: International journal of biological macromolecules 2021-01, Vol.166, p.1082-1095
• Main Authors: Azimi, Fateme, Ghasemi, Jahan B., Azizian, Homa, Najafi, Mohammad, Faramarzi, Mohammad Ali, Saghaei, Lotfollah, Sadeghi-aliabadi, Hojjat, Larijani, Bagher, Hassanzadeh, Farshid, Mahdavi, Mohammad
• Format: Article
• Language: English
• Subjects: alpha-Glucosidases - chemistry; alpha-Glucosidases - metabolism; Binding Sites; Drug Design; Enzyme kinetic study; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - pharmacology; Kinetics; Molecular Docking Simulation; Molecular dynamic simulation; Phenols - chemistry; Protein Binding; Pyrazoles - chemistry; Pyrezole; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - metabolism; Semicarbazones - chemistry; Structure-Activity Relationship; Synthesize; α-Glucosidase inhibitor
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2020.10.263

A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the α-glucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast α-glucosidase inhibition (IC50 values in the range of 65.1–695.0 μM) even much more potent than standard drug acarbose (IC50 = 750.0 μM). Among them, compounds 8o displayed the most potent α-glucosidase inhibitory activity (IC50 = 65.1 ± 0.3 μM). Kinetic study of compound 8o revealed that it inhibited α-glucosidase in a competitive mode (Ki = 87.0 μM). 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 silico 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).