2. Academic Validation
  3. A new framework for novel analogues of pazopanib as potent and selective human carbonic anhydrase inhibitors: Design, repurposing rational, synthesis, crystallographic, in vivo and in vitro biological assessments

A new framework for novel analogues of pazopanib as potent and selective human carbonic anhydrase inhibitors: Design, repurposing rational, synthesis, crystallographic, in vivo and in vitro biological assessments

  • Eur J Med Chem. 2024 Aug 5:274:116527. doi: 10.1016/j.ejmech.2024.116527.
Salma M Hefny 1,  Tarek F El-Moselhy 2,  Nabaweya El-Din 2,  Andrea Ammara 3,  Andrea Angeli 3,  Marta Ferraroni 4,  Ahmed M El-Dessouki 5,  Moataz A Shaldam 6,  Galal Yahya 7,  Ahmed A Al-Karmalawy 8,  Claudiu T Supuran 9,  Haytham O Tawfik 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt. Electronic address: [email protected].
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt.
  • 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 University of Florence, Department of Chemistry, Via della Lastruccia, 50019, Sesto Fiorentino, Italy.
  • 5 Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
  • 7 Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia, 44519, Egypt; Molecular Biology Institute of Barcelona, Spanish National Research Council (IBMB-CSIC), 08028, Barcelona, Catalonia, Spain.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, 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: [email protected].
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt. Electronic address: [email protected].
PMID: 38810335 DOI: 10.1016/j.ejmech.2024.116527
Abstract

Herein, we describe the design and synthesis of novel aryl pyrimidine benzenesulfonamides APBSs 5a-n, 6a-c, 7a-b, and 8 as pazopanib analogues to explore new potent and selective inhibitors for the CA IX. All APBSs were examined in vitro for their promising inhibition activity against a small panel of hCAs (isoforms I, II, IX, and XII). The X-ray crystal structure of CA I in adduct with a representative APBS analogue was solved. APBS-5m, endowed with the best hCA IX inhibitory efficacy and selectivity, was evaluated for antiproliferative activity against a small panel of different Cancer cell lines, SK-MEL-173, MDA-MB-231, A549, HCT-116, and HeLa, and it demonstrated one-digit IC50 values range from 2.93 μM (MDA-MB-231) to 5.86 μM (A549). Furthermore, compound APBS-5m was evaluated for its influence on hypoxia-inducible factor (HIF-1α) production, Apoptosis induction, and colony formation in MDA-MB-231 Cancer cells. The in vivo efficacy of APBS-5m as an antitumor agent was additionally investigated in an animal model of Solid Ehrlich Carcinoma (SEC). In order to offer perceptions into the conveyed hCA IX inhibitory efficacy and selectivity in silico, a molecular docking investigation was also carried out.

Keywords

Aryl pyrimidine benzene sulfonamides (APBSs); Hypoxic solid tumors; In silico studies; X-ray crystallography; hCA IX inhibitors.

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