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  3. Development of 4-((3-oxo-3-phenylpropyl)amino)benzenesulfonamide derivatives utilizing tail/dual-tail approaches as novel carbonic anhydrase inhibitors

Development of 4-((3-oxo-3-phenylpropyl)amino)benzenesulfonamide derivatives utilizing tail/dual-tail approaches as novel carbonic anhydrase inhibitors

  • Eur J Med Chem. 2022 Aug 5;238:114412. doi: 10.1016/j.ejmech.2022.114412.
Mostafa M Elbadawi 1,  Wagdy M Eldehna 2,  Alessio Nocentini 3,  Warda R Somaa 4,  Sara T Al-Rashood 5,  Eslam B Elkaeed 6,  Mahmoud A El Hassab 7,  Hatem A Abdel-Aziz 8,  Claudiu T Supuran 9,  Mohamed Fares 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt; School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt. Electronic address: wagdy2000@gmail.com.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 4 Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
  • 5 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
  • 6 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), South Sinai, Egypt.
  • 8 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.
  • 9 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt; School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia.
PMID: 35551035 DOI: 10.1016/j.ejmech.2022.114412
Abstract

In the current work, we adopted the tail/dual tail approaches to design and synthesize the benzenesulfonamide derivatives 6a-b, 8, 10a-b, 12a-b, 14, and 16 as new SLC-0111 analogs endowed with Carbonic Anhydrase (CA) inhibitory activity. All the prepared benzenesulfonamide derivatives were tested for their inhibitory action towards hCA isoforms; hCA I, II, IX, and XII. The results revealed their ability to affect the examined isoforms in variable degrees with KI ranges: 49.3-6459 nM for CA I, 5.1-4171 nM for CA II, 9.4-945.1 nM for CA IX, and 5.2-1159 nM for CA XII. As expected, appending a second hydrophilic tail (ethanolamine) in compound 16 significantly enhanced the inhibitory activities towards hCA IX and hCA XII isoforms by about 5-fold in comparison to its single tail analogue 6c (KI = 51.5 and 28.2 nM for 6cvs. 10.2 and 5.2 nM for 16, respectively). Moreover, SAR analysis pointed out the significance of grafting the sulfamoyl functionality at para-position, as well as the incorporation of a bulky hydrophobic tail for CA inhibitory activity. The most potent hCA IX inhibitors (6f and 16) displayed efficient cell growth inhibitory activity against breast Cancer cell lines; T-47D (IC50 = 19 and 10.9 μM, respectively) and MCF-7 (IC50 = 7.5 and 5.7 μM, respectively).

Keywords

Benzenesulfonamide; Carbonic anhydrase inhibitors; Dual-tail approach; Hypoxic tumors; SLC-0111 analogues.

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