New imidazole-2-ones and their 2-thione analogues as anticancer agents and CAIX inhibitors: Synthesis, in silico ADME and molecular modeling studies

Abstract

The present study involves the synthesis of a series of new imidazole-2-ones derivatives and their 2-thione analogs using conventional heating and the environmentally friendly benign technique, the microwave technique. Structure of the compounds was well elucidated by considering the data of both elemental and spectral analyses. The obtained data and theoretical values of the synthesized molecules correlated with the proposed molecular structure. Moreover, all the synthesized compounds were evaluated in vitro for antitumor activity against HCT-116 and HeP2 human cancer cell panels and assessed as selective carbonic anhydrase IX isozyme (CA9/CAIX) inhibitors, thereby providing useful preliminary evidence for drug development. In addition, computational techniques were used to investigate the molecular and electronic characteristics of the investigated organic compounds. The 4b compound exhibited the best quantum chemistry features, as the highest occupied molecular orbital, softness, energy gap, and dipole moment, indicating the highest biological activity. This was supported by the experimental findings. Moreover, the in silico evaluation of drug candidates was also investigated. Thereafter, the anticancer activity of the most reactive candidate was studied via molecular docking to determine the types of interactions between this molecule and CAIX. According to the docking experiments, the 4b molecule generates five hydrogen bond interactions with active amino acid residues, Gln 92, Gln 67, and Thr 200.

Keywords: Antitumor activity; Carbonic anhydrase; DME; Docking Simulation Quantum Calculations; Imidazole-2-ones; Imidazole-2-thiones.