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  3. Development of novel benzofuran-based SLC-0111 analogs as selective cancer-associated carbonic anhydrase isoform IX inhibitors

Development of novel benzofuran-based SLC-0111 analogs as selective cancer-associated carbonic anhydrase isoform IX inhibitors

  • Eur J Med Chem. 2021 Apr 15:216:113283. doi: 10.1016/j.ejmech.2021.113283.
Moataz Shaldam 1,  Wagdy M Eldehna 2,  Alessio Nocentini 3,  Zainab M Elsayed 4,  Tamer M Ibrahim 5,  Rofaida Salem 1,  Ramadan A El-Domany 6,  Clemente Capasso 7,  Hatem A Abdel-Aziz 8,  Claudiu T Supuran 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt; Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 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 Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt; Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 6 Department of Microbiology and Immunology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 7 Institute of Biosciences and Bioresources, CNR, Via Pietro Castellino 111, 80131, Napoli, Italy.
  • 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.
PMID: 33667848 DOI: 10.1016/j.ejmech.2021.113283
Abstract

In the present study, we describe the design of different series of benzofuran-based derivatives as potential Carbonic Anhydrase inhibitors (CAIs). The adopted design is based on bioisosteric replacement for the p-fluorophenyl SLC-0111 tail with the lipophilic 2-methylbenzofuran or 5-bromobenzofuran tails to furnish the 2-methylbenzofuran (MBF) sulfonamides (MBFS; 9, 11 and 13) and 5-bromobenzofuran (BBF) sulfonamides (BBFS; 27a-b, 28a-b and 29a-c), respectively. Thereafter, the urea spacer was either elongated to furnish MBFS (17 and 19), and BBFS (30) series, or replaced by a carbamate one to afford MBFS (15). All the designed compounds were synthesized and evaluated for their inhibitory activities against four human (h) CA isoforms: hCA I, II, IX and XII. MBFS (11b and 17) and BBFS (28b, 29a and 30) efficiently inhibited the tumor-related CA IX isoform in the single-digit nanomolar range (KIs = 8.4, 7.6, 5.5, 7.1 and 1.8 nM, respectively). In particular, MBFS 11b and BBFS 28b exhibited good selectivity toward hCA IX isoform over the main off-target hCA II isoform (S.I. = 26.4 and 58.9, respectively). As a consequence, 11b and 28b were examined for their Anticancer and pro-apoptotic activities toward MDA-MB-231 and MCF-7 Cancer cell lines.

Keywords

Benzofuran synthesis; Carbonic anhydrase inhibitors; Diaryl urea; Molecular modeling; SLC-0111 analogs; Tail approach.

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