2. Academic Validation
  3. 3-Methylthiazolo[3,2-a]benzimidazole-benzenesulfonamide conjugates as novel carbonic anhydrase inhibitors endowed with anticancer activity: Design, synthesis, biological and molecular modeling studies

3-Methylthiazolo[3,2-a]benzimidazole-benzenesulfonamide conjugates as novel carbonic anhydrase inhibitors endowed with anticancer activity: Design, synthesis, biological and molecular modeling studies

  • Eur J Med Chem. 2020 Dec 1;207:112745. doi: 10.1016/j.ejmech.2020.112745.
Abdulsalam A M Alkhaldi 1,  Mohammad M Al-Sanea 2,  Alessio Nocentini 3,  Wagdy M Eldehna 4,  Zainab M Elsayed 5,  Alessandro Bonardi 3,  Mahmoud F Abo-Ashour 6,  Ashraf K El-Damasy 7,  Mohammed S Abdel-Maksoud 8,  Tarfah Al-Warhi 9,  Paola Gratteri 10,  Hatem A Abdel-Aziz 11,  Claudiu T Supuran 12,  Radwan El-Haggar 13
Affiliations

Affiliations

  • 1 Biology Department, College of Science, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia.
  • 2 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 4 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: [email protected].
  • 5 Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt.
  • 7 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 8 Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC (ID: 60014618)), Dokki, Giza, 12622, Egypt.
  • 9 Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
  • 10 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 11 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.
  • 12 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: [email protected].
  • 13 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795, Cairo, Egypt.
PMID: 32877804 DOI: 10.1016/j.ejmech.2020.112745
Abstract

Herein we describe design and synthesis of different series of novel small molecules featuring 3-methylthiazolo[3,2-a]benzimidazole moiety (as a tail) connected to the zinc anchoring benzenesulfonamide moiety via ureido (7), enaminone (12), hydrazone (14), or hydrazide (15) linkers. The newly prepared conjugates have been screened for their inhibitory activities toward four human (h) Carbonic Anhydrase (CA, EC 4.2.1.1) isoforms: hCA I, II, IX and XII. Thereafter, the urea and enaminone linkers were elongated by one- or two-atoms spacers to afford the elongated counterparts 9 and 13, respectively. Finally, the zinc anchoring sulfonamide group was replaced by the carboxylic acid group to afford acids 17. Compounds 12d, 13b and 15 displayed single-digit nanomolar CA IX inhibitory activities (KIs = 6.2, 9.7 and 5.5 nM, respectively), along with good selectivity towards hCA IX over hCA I and II. Subsequently, they were screened for their growth inhibitory actions against breast Cancer MCF-7 and MDA-MB-231 cell lines, and for their impact on cell cycle progression and induction of Apoptosis. Moreover, a molecular docking study was conducted to gain insights for the plausible binding interactions of target sulfonamides within hCA isoforms II, IX and XII binding sites.

Keywords

Anticancer agents; Carbonic anhydrase inhibitors; Molecular modeling; SLC-0111 analogues; Tail approach; thiazolo[3,2-a]benzimidazole.

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