2. Academic Validation
  3. Discovery of new sulfonamide-tethered 2-aryl-4-anilinoquinazolines as the first-in-class dual carbonic anhydrase and EGFR inhibitors

Discovery of new sulfonamide-tethered 2-aryl-4-anilinoquinazolines as the first-in-class dual carbonic anhydrase and EGFR inhibitors

  • Int J Biol Macromol. 2024 Nov;279(Pt 2):135010. doi: 10.1016/j.ijbiomac.2024.135010.
Wagdy M Eldehna 1,  Zainab M Elsayed 2,  Andrea Ammara 3,  Mahmoud A El Hassab 4,  Hadia Almahli 5,  Mohamed Fares 6,  Alessio Nocentini 3,  Claudiu T Supuran 7,  Sahar M Abou-Seri 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt. Electronic address: wagdy2000@gmail.com.
  • 2 Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Firenze, Italy.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), South Sinai, Egypt.
  • 5 Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, ERU, Badr City, Cairo 11829, Egypt.
  • 7 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt. Electronic address: sahar.shaarawy@pharma.cu.edu.eg.
PMID: 39197616 DOI: 10.1016/j.ijbiomac.2024.135010
Abstract

In today's medical field, there is a growing trend of exploiting a single small molecule to target two different molecular targets concurrently. This approach is proving to be highly effective in fighting against Cancer. The 4-anilinoquinazoline scaffold, known for its potential in Cancer therapy and its effectiveness as a leading class of tyrosine kinase inhibitors, was employed to develop a novel series of anilinoquinazoline-sulfonamides (AQSs) (8a-d, 9a-f, and 10a-d) as dual inhibitors of the tumor-associated carbonic anhydrases (CA) IX/XII and EGFR. 2-(3-Methoxyphenyl)quinazoline bearing p-sulfanilamide 10b elicited superior hCA IX and XII inhibition in the low nanomolar range (KIs = 38.4 and 8.9 nM, respectively). Also, 10b shined as a potent and selective EGFR inhibitor, boasting an impressive IC50 value of 51.2 ± 0.97 nM, surpassing the reference EGFR inhibitor Erlotinib (IC50 = 80 ± 2.0 nM). Compound 10b exhibited broadest-spectrum antiproliferative activity against the NCI-tumor panel with a mean GI% value of 68 %. Of special interest, 10b demonstrated potent growth inhibition (GI% ≥ 80-97 %) toward cell lines reported to express high levels of EGFR belonging to renal, colon, breast, and lung cancers. Compound 10b's molecular docking in the CA IX/XII and EGFR active sites revealed binding modes that justify its potent Enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated strong and stable interactions of 10b with the binding sites of these targets.

Keywords

4-Aminoquinazolines; Hypoxic tumors; Kinase inhibitor; Molecular dynamics; Synthesis.

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