The synthesis, biological evaluation and in silico studies of asymmetric 3,5-diaryl-rhodanines as novel inhibitors of human carbonic anhydrase isoenzymes

Abstract

The synthesis of rhodanine core, which forms the main skeleton of organics used as a large number of drugs, is obtained with more green approaches is very significant. Additionally, asymmetrical functionalization from C5 and N(3) positions of 3-NH2-Rh (1) via a green approach is representing a challenge. In this connect, the primary goal of this study is to obtain novel asymmetric 3,5-diarylRhs by an effective green synthetic approach. For this, initially, the reactions of the variety of aromatic aldehydes with 5-Ar-Rhs 2a and 2b were investigated by changing parameters such as catalyst, solvent, and temperature. As a result of the studies, novel asymmetric 3,5-diarylRhs were obtained as the main product of acetic acid catalyst reactions carried out at reflux temperatures of ethanol. Moreover, the site-selective reduction of the imine group in the structure of the asymmetric 3,5-diarylRhs was also carried out within the scope of this study. Following synthesis, we also carried out inhibition studies of novel 3,5-diarylRhs against cytosolic human carbonic anhydrase I, and II (hCA I and II) isoforms. As a result of these inhibition studies, inhibition constants (Ki) for hCA I and hCA II were found in the range of 107.26 ± 31.18 to 601.97 ± 46.44 nM, and 127.72 ± 15.75 to 480.13 ± 47.24 nM, respectively. In order to support the results obtained as a result of the inhibition studies, molecular docking studies of the asymmetrical 3,5-diarylRhs 4i and 4l showing the best activity for hCA I and hCA II were also carried out, and the morphology of the binding was examined. Furthermore, the organics comply with Lipinski’s and Jorgensen’s rules of all compounds were determined by calculated ADME and drug-likeness parameters. That is, the ADME and drug-likeness parameters of the new 3,5-diarylRhs showed that they are not only with hCA I and hCA II inhibitory activities but also with appropriate drug-likeness properties and physicochemical parameters.