4.7 Article

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

Journal

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 216, Issue -, Pages -

Publisher

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113283

Keywords

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

Funding

  1. CNR, Italy
  2. ASRT, Egypt

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This study describes the design of benzofuran-based derivatives as potential carbonic anhydrase inhibitors, with modifications in tail and spacer structures to enhance inhibitory activities against tumor-related CA isoforms. The synthesized compounds showed efficient inhibition of CA IX isoform and promising anticancer and pro-apoptotic activities towards cancer cell lines.
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 (K(I)s = 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

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