Sulfonamide-phosphonate hybrids as new carbonic anhydrase inhibitors: In vitro enzymatic inhibition, molecular modeling, and ADMET prediction

In the presented work, we report the synthesis of a new series of sulfonamide-phosphonate hybrids 4a-m. These newly synthesized compounds were assessed for their inhibitory effects toward two human carbonic anhydrase isoforms I and II (hCA I and II). These examined isoforms were as well inhibited by the most of prepared sulfonamide-phosphonates in comparison to standard inhibitor acetazolamide. Obtained data exhibited that compounds 4b-m with K-i values in the range of 8.11-48.08 nM were more potent than standard drug acetazolamide with K-i value of 64.52 Nm against hCA I. Moreover, all the synthesized compounds (K-i values = 7.08-64.24 nM), with the exception of compound 4b, were more potent than acetazolamide (K-i value = 75.36) against hCA II. In particular, sulfonamide-phosphonates 4l and 4j, respectively, with substituents 5-chloro-2-nitro and 2,3-dichloro emerged as the most potent hCA inhibitors. Thereafter, the molecular docking of compounds 4l and 4j at hCA I and II active sites was performed and the obtained results revealed that these compounds interacted whit the important amino acids of the active site. Finally, the predicted parameters of Lipinski's rule of five, ADME, and toxicity analysis showed that compounds 4l and 4j had good drug-likeness and acceptable physicochemical properties. Therefore, the hybridization of the sulfonamide and phosphonate moieties could be promising strategy for achieve to potent lead compounds for inhibition of hCA. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

In this study, a series of new sulfonamide-phosphonate hybrids were synthesized and evaluated for their inhibitory effects on carbonic anhydrase enzymes. The results demonstrated that these compounds exhibited potent inhibitory activity against human carbonic anhydrase, with certain compounds showing even greater potential. Molecular docking studies further revealed significant interactions between these compounds and the active site of the enzymes.