Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors

Mudasir Nabi Peerzada; Daniela Vullo; Niccolò Paoletti; Alessandro Bonardi; Paola Gratteri; Claudiu T Supuran; Amir Azam

doi:10.1021/acsmedchemlett.3c00094

Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors

ACS Med Chem Lett. 2023 May 8;14(6):810-819. doi: 10.1021/acsmedchemlett.3c00094. eCollection 2023 Jun 8.

Authors

Mudasir Nabi Peerzada¹, Daniela Vullo², Niccolò Paoletti², Alessandro Bonardi², Paola Gratteri², Claudiu T Supuran², Amir Azam¹

Affiliations

¹ Medicinal Chemistry and Drug Discovery Research Laboratory, Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India.
² Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.

Abstract

To discover novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors for cancer treatment, a series of 4-{4-[(hydroxyimino)methyl]piperazin-1-yl}benzenesulfonamides were designed and synthesized using SLC-0111 as the lead molecule. The developed novel compounds 27-34 were investigated for the inhibition of human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. The hCA I was inhibited by compound 29 with a K_i value of 3.0 nM, whereas hCA II was inhibited by compound 32 with a K_i value of 4.4 nM. The tumor-associated hCA IX isoform was inhibited by compound 30 effectively with an K_i value of 43 nM, whereas the activity of another cancer-related isoform, hCA XII, was significantly inhibited by 29 and 31 with a K_i value of 5 nM. Molecular modeling showed that drug molecule 30 participates in significant hydrophobic and hydrogen bond interactions with the active site of the investigated hCAs and binds to zinc through the deprotonated sulfonamide group.