Synthesis, biological evaluation and molecular docking studies of new pyrimidine derivatives as potent dual EGFR/HDAC inhibitors

• Published in: Journal of molecular structure Vol. 1309; p. 138223
• Main Authors: Sivaiah, G., Raghu, M.S., Prasad, S.B. Benaka, Anusuya, A.M., Kumar, K. Yogesh, Alharethy, Fahd, Prashanth, M.K., Jeon, Byong-Hun
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.08.2024
• Subjects: Anticancer; EGFR; HDAC; Molecular docking; Pyrimidine; Anticancer; EGFR; Molecular docking; Pyrimidine; HDAC
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.138223

•A series of diversly functionalized pyrimidine derivatives were synthesized.•The synthesized compounds were characterized by spectroscopic and analytical techniques.•They were screened for their anticancer activity against MCF-7 and HepG2 cell line.•Promising cytotoxic compounds 5a, 5c, 5 g, 5 h and 5i were tested for EGFR and HDAC inhibition studies.•Molecular docking in the EGFR, HDAC1 and HDAC6 active site confirmed the obtained activity. Pyrimidine scaffolds are an exceptional kind of heterocyclic ring that may be used to create and develop novel anticancer drugs. As a result, the current work described the design and synthesis of novel pyrimidine derivatives (5a-j) as potent dual inhibitors of epidermal growth factor receptor (EGFR) and integrating histone deacetylase (HDAC). Using elemental analysis and spectroscopic techniques, the structure of the newly synthesized compounds was elucidated. All the compounds were tested in vitro against MCF-7, HepG2 and A549 cell lines for their antiproliferative properties. Compared to the reference medication erlotinib, compounds 5 h and 5i demonstrated remarkably improved effectiveness against MCF-7, HepG2 and A549 cell lines and better safety towards normal WI-38 cells. The EGFR and HDAC inhibitory effects of compounds 5a, 5c, 5 g, 5 h, and 5i were assessed. With IC50 values of 8.43 and 6.91 nM, respectively, the compounds 5 h and 5i demonstrated considerable inhibition against EGFR L858R/T790M mutant kinase. Compound 5i had a strong inhibitory effect compared to reference drug Vorinostat (SAHA) against the investigated isoenzymes of HDAC1, HDAC2, HDAC4, and HDAC6 with an IC50 values of 22.73, 20.08, 3100, and 3.71 nM, respectively. Additionally, docking studies were performed to determine the binding mode of potent compounds 5 h and 5i, towards the potential target EGFR, HDAC1 and HDAC6 proteins. Furthermore, all of these results suggested that the target compounds 5 h and 5i might be seen as viable lead candidates for the dual inhibition of both EGFR and HDAC enzymes, which would enable the identification of novel anticancer agents. [Display omitted]