Preparation, structure determination, and in silico and in vitro Elastase inhibitory properties of substituted N-([1,1′-Biphenyl]-2-ylcarbamothioyl)-Aryl/Alkyl benzamide Derivatives

The preparation of a set of eight closely related biphenyl-thiourea conjugates with aromatic and aliphatic side chains (3a-3h) using a one-pot three-component strategy is reported. All the novel compounds were characterized by spectroscopic techniques (FTIR, H-1 and C-13 NMR) and elemental analysis. Moreover, the crystal structure of compounds 3f and 3h have been determined by X-ray diffraction. The common molecular skeleton can be closely superposed to each other and the 1-acyl thiourea groups show a nearly planar conformation favored by an intramolecular N-H center dot center dot center dot O=C bond. In-vitro studies were carried out to test the elastase inhibition activity of the newly synthesized biphenyl-thiourea hybrid derivatives. Among the series, compound 3c (IC50 = 0.26 +/- 0.05 mu M) exhibited the maximum inhibition against elastase. The higher activity of aryl substituents over alkyl chains is evidenced, as well as the importance of electron withdrawing groups, as nitro (3b and 3c) and bromo (3d) to enhance the enzyme inhibitory activity. The compound 3c inhibits the enzyme in a competitive manner, with dissociation constant K-i = 0.84 mu M. Molecular docking was also carried out within the enzyme active site to study enzyme-inhibitor interactions. Docking results correlate with experimental inhibition studies and show that compound 3c exhibits the highest binding energy (-7.70 kcal/mol) as compared with other compounds. The results of this study might help to develop new elastase inhibitors. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

A series of closely related biphenyl-thiourea conjugates with aromatic and aliphatic side chains were synthesized using a one-pot three-component strategy. In vitro studies showed compound 3c exhibited the highest inhibition against elastase, highlighting the importance of aryl substituents over alkyl chains in enhancing enzyme inhibitory activity. Molecular docking results revealed compound 3c exhibited the highest binding energy compared to other compounds, suggesting its potential as a new elastase inhibitor.