The solvent-controlled regioselective synthesis of 3-amino-5-aryl-rhodanines as novel inhibitors of human carbonic anhydrase enzymes

The regioselective functionalization from C5-position instead of more nucleophilic NH2 of 3-NH2-Rh (1) via a green approach is representing a challenge. The primary goal of this study is to develop the solvent -promoted and-controlled regioselective bond alkylation reactions of 3-NH2-Rh (1) with NH2 free-rhodanine (1) under catalyst-free conditions. In the presence of water as the solvent, C5-addition ary-lation reactions of 3-NH2-Rh (1) with aldehydes efficiently gave C5-arylated-rhodanine (5-Ar-Rhs). On the other hand, using catalytic amounts of an acid catalyst in ethanol, the reaction of 3-NH2-Rh (1) and aldehydes resulted in the arylation of rhodanine at the NH-position. Water plays two roles in the re-actions: converting the 3-NH2-Rh (1) into bidentate nucleophiles and activating the C-5 position of 3-NH2-Rh (1) to achieve the Knoevenagel condensation via hydrogen bond clusters. The 3-NH2-Rh (1) act as a C-nucleophile due to the H-bond clusters between water and the amino group of 3-NH2-Rh (1), whereas upon using catalytic amounts of CH3CO2H in pure ethanol the compounds act as an NH2- nucleophile. Moreover, the enzyme inhibition studies of novel 5-Ar-Rhs against cytosolic carbonic anhydrase (hCAs) I, and II isoforms was carried out. As a result of these biological studies, inhibition constants (Ki) for hCA I and hCA II were found in the range of 239.88 +/- 79.31 to 610.24 +/- 111.43 nM, and 262.69 +/- 13.20 to 638.10 +/- 127.73 nM, respectively. (c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

This study achieved the solvent-promoted regioselective bond alkylation reactions between 3-NH2-Rh and NH2 free-rhodanine under catalyst-free conditions. Water played a crucial role in the reactions and the synthesized 5-Ar-Rh compounds exhibited inhibition activity against cytosolic carbonic anhydrase.