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  3. Novel dihydropyrimidines as promising EGFR & HER2 inhibitors: Insights from experimental and computational studies

Novel dihydropyrimidines as promising EGFR & HER2 inhibitors: Insights from experimental and computational studies

  • Eur J Med Chem. 2024 Sep 5:275:116607. doi: 10.1016/j.ejmech.2024.116607.
Syed Faizan 1,  Adil Farooq Wali 2,  Sirajunisa Talath 2,  Muneeb U Rehman 3,  Yuvaraj Sivamani 1,  Kiran C Nilugal 4,  Narendra Babu Shivangere 4,  Sabry M Attia 5,  Ahmed Nadeem 5,  Sumitha Elayaperumal 6,  B R Prashantha Kumar 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570015, Constituent College of the JSS Academy of Higher Education & Research, Mysuru, 570015, India.
  • 2 Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical & Health Sciences University, Ras Al Khaimah, United Arab Emirates.
  • 3 Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
  • 4 School of Pharmacy, Management and Science University, Selangor, 40100, Malaysia.
  • 5 Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
  • 6 Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysore, Karnataka, India.
  • 7 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570015, Constituent College of the JSS Academy of Higher Education & Research, Mysuru, 570015, India. Electronic address: brprashanthkumar@jssuni.edu.in.
PMID: 38908102 DOI: 10.1016/j.ejmech.2024.116607
Abstract

Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast Cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.

Keywords

3D-QSAR; Breast cancer; CoMSIA; Dihydropyrimidines; Drug discovery; EGFR inhibitors; HER2 inhibitors.

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