Molecular hybrids integrated with imidazole and hydrazone structural motifs: Design, synthesis, biological evaluation, and molecular docking studies

Abstract

In the present work, a series of compounds containing imidazole and hydrazone structural frameworks were synthesized and characterized using various spectral techniques, including 1H NMR, 13C NMR, FTIR, and HRMS. Synthesized compounds were subjected to screening as antiproliferative agents as well as against two physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I and hCA II. Among them, some compounds exhibited remarkable antiproliferative activity with less cytotoxicity activity to healthy cells and significant CA inhibitory activities in contrast to a standard inhibitor with Ki values in the range of 0.49 ± 1.010–739.12 ± 111.35 nM for hCA I (Ki value for standard inhibitor = 271.15 ± 74.620 nM), 64.53 ± 19.44–314.37 ± 54.78 nM for hCA II (Ki value for standard inhibitor = 113.07 ± 20.980 nM). In addition, DFT calculations were performed to get insight into the distinctive reactive sites of all compounds, and subsequently, the reactive centers of the compounds were determined. Moreover, molecular docking studies of the most potent compounds were conducted, and results showed reasonable binding modes in the active sites of hCA I protein (PDB ID: 2CAB), hCA II protein (PDB ID: 3DC3), as well as colon cancer protein (PDB ID: 4UYA and 3DTC). Finally, in silico predictions of ADME and pharmacokinetic parameters indicated that these compounds should have good oral bioavailability.