4-Anilinoquinazoline-based benzenesulfonamides as nanomolar inhibitors of carbonic anhydrase isoforms I, II, IX, and XII: design, synthesis, in-vitro, and in-silico biological studies

Abstract

Human carbonic anhydrase inhibitors (hCAIs) are a key therapeutic class with a multitude of novel applications such as anticonvulsants, topically acting antiglaucoma, and anticancer drugs. Herein, a new series of 4-anilinoquinazoline-based benzenesulfonamides were designed, synthesised, and biologically assessed as potential hCAIs. The target compounds are based on the well-tolerated kinase scaffold (4-anilinoquinazoline). Compounds 3a (89.4 nM), 4e (91.2 nM), and 4f (60.9 nM) exhibited 2.8, 2.7, and 4 folds higher potency against hCA I when compared to the standard (AAZ, V), respectively. A single digit nanomolar activity was elicited by compounds 3a (8.7 nM), 4a (2.4 nM), and 4e (4.6 nM) with 1.4, 5, and 2.6 folds of potency compared to AAZ (12.1 nM) against isoform hCA II, respectively. Structure-activity relationship (SAR) and molecular docking studies validated our design approach that revealed highly potent hCAIs.

Keywords:

• Quinazoline-benzenesulfonamide hybrids
• Suzuki coupling
• Carbonic anhydrase inhibitors
• Molecular docking

Acknowledgements

A.E. expresses his gratitude to the Korea Institute of Science and Technology (KIST) for partially supporting this work through the “2022 KIST School Partnership Project,” and he would like to thank the Technology Innovation Commercial Office (TICO) at Mansoura University for their highly effective contribution to the project’s success. M.H.A. would like to thank Taif University Researchers Project number (TURSP-2020/91), Taif University, Taif, Saudi Arabia.

Disclosure statement

CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [No. 2018R1A5A2023127] and the BK21 FOUR program funded by the Ministry of Education of Korea through NRF.