Synthesis, molecular docking and QSAR study of thiazole clubbed pyrazole hybrid as α-amylase inhibitor

In search of potent alpha-amylase inhibitors, herein we report the synthesis, molecular docking and QSAR study of some thiazole clubbed pyrazole hybrids (TCPH) i.e., 1-((1-phenyl-3-aryl-1H-pyrazole-4-yl)methylene)-2-(4-arylthiazole-2-yl)hydrazine (4a-4r) as an alpha-amylase inhibitors. Among the different analogues, compounds 4g and 4h were found to be most potent at 50 mu g/mL with 89.15% and 88.42% of inhibition. The Monte Carlo optimisation method was applied to build robust QSAR models for the prediction of percentage inhibition of TCPH at different concentration with various statistical parameters. The Simplified Molecular Input Line Entry System (SMILES) was applied to symbolise the molecular structure, descriptor calculation and model development. The role of the index of ideality correlation (IIC) was also studied which revealed a model for split 3 as a leading model with best R-2 i.e., 0.9198. The compound 4l at different concentration (TCPH11, TCPH29 and TCPH47) was outside the applicability domain (AD) for the developed QSAR models for split 4 only. The SMILES attributes at three different concentrations were also detected. These attributes are the promoters of percentage increase/decrease in inhibition efficiency of the inhibitors. The docking simulation of most active compounds (4g and 4h) were performed within the active site of Aspergillus oryzae alpha-amylase (PDB ID: 7TAA) to analyse the binding conformation and interactions responsible for their activity. As a result, it was found that the binding interactions found between 4g, 4h and alpha-amylase were similar to those responsible for alpha-amylase inhibition by acarbose. Communicated by Ramaswamy H. Sarma

Automated summary

In this study, novel alpha-amylase inhibitors in the form of pyrazole clubbed thiazole hybrids were synthesized, with compounds 4g and 4h showing the highest inhibition rates at 50 μg/mL. QSAR models and docking simulations were used to understand the binding interactions and mechanisms responsible for the activity of these compounds against alpha-amylase.