2. Academic Validation
  3. Application of the dual-tail approach for the design and synthesis of novel Thiopyrimidine-Benzenesulfonamide hybrids as selective carbonic anhydrase inhibitors

Application of the dual-tail approach for the design and synthesis of novel Thiopyrimidine-Benzenesulfonamide hybrids as selective carbonic anhydrase inhibitors

  • Eur J Med Chem. 2022 Jan 15;228:114004. doi: 10.1016/j.ejmech.2021.114004.
Heba T Abdel-Mohsen 1,  Ahmed M El Kerdawy 2,  Mohamed A Omar 3,  Andrea Petreni 4,  Rasha M Allam 5,  Hoda I El Diwani 3,  Claudiu T Supuran 6
Affiliations

Affiliations

  • 1 Department of Chemistry of Natural and Microbial Products, Pharmaceutical and Drug Industries Research Institute, National Research Centre, El-Buhouth St., Dokki, P.O. Box 12622, Cairo, Egypt. Electronic address: ht.abdel-mohsen@nrc.sci.eg.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, School of Pharmacy, Newgiza University (NGU), NewGiza, Km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.
  • 3 Department of Chemistry of Natural and Microbial Products, Pharmaceutical and Drug Industries Research Institute, National Research Centre, El-Buhouth St., Dokki, P.O. Box 12622, Cairo, Egypt.
  • 4 Università Degli Studi di Firenze, Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy.
  • 5 Department of Pharmacology, National Research Centre, El-Buhouth St., Dokki, P.O. Box 12622, Cairo, Egypt.
  • 6 Università Degli Studi di Firenze, Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
PMID: 34847409 DOI: 10.1016/j.ejmech.2021.114004
Abstract

A dual-tail approach was applied to the design of a novel series of 2-thiopyrimidine-benzenesulfonamides as Carbonic Anhydrase (CA) inhibitors. The design strategy is based on the hybridization between a benzenesulfonamide moiety as Zn2+ binding group and 2,4-disubstituted thiopyridimidine as a tail. Among the synthesized compounds, 14h displayed the highest potency (Ki = 1.72 nM) and selectivity for CA II over the isoforms CA IX and CA XII with selectivity indexes of 50 and 5.26, respectively. Meanwhile, compounds 14a and 14l displayed a potent inhibitory activity against CA IX (Ki = 7.4 and 7.0 nM, respectively) compared with the reference drug acetazolamide (AAZ) (Ki = 25 nM), and compound 14l showed higher potency (Ki = 4.67 nM) than AAZ (Ki = 5.7 nM) against the tumor-associated isoform CA XII. Evaluation of the antiproliferative activity in NCI single-dose testing of selected hybrids revealed a pronounced potency of the selective CA II inhibitor 14h against most of the tested NCI Cancer cell lines. Moreover, compound 14h demonstrated an IC50 values ranging from 2.40 to 4.50 μM against MCF-7, T-47D, MDA-MB-231, HCT-116, HT29 and SW-620. These results demonstrate that CA II inhibition can be an alternative therapeutic target for Cancer treatment. A cell cycle analysis of MCF-7 and MDA-MB-231 showed that treatment with 14h arrested both cell lines at the G2/M phase with significant accumulation of cells in the pre-G1 phase. Moreover, compound 14h showed a noticeable induction of late Apoptosis and necrotic cell death of both cell lines compared with untreated cells as a control. A molecular docking study suggested that the sulfonamide moiety accommodates deeply in the CA active site and interacts with the Zn2+ ion while the dual-tail extension interacts with the surrounding Amino acids via several hydrophilic and hydrophobic interactions, which affects the potency and selectivity of the hybrids.

Keywords

Antiproliferative activity; Carbonic anhydrase inhibitors; Dual-tail approach; Thiopyrimidine-benzenesulfonamide hybrids.

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