Compound 6b(The British University in Egypt (BUE))

Cancer remains one of the most significant health challenges worldwide. Despite the continuous development of anticancer drugs, the battle against cancer persists due to frequent mutations. Tropomyosin receptor kinase A (TrkA) is considered one of the promising targets in cancer therapy. The urge to overcome drug resistance has prioritized the need for synthesizing potent TrkA inhibitors. In this study, we synthesized a series of sixteen novel pyrimidinone derivatives that showed potent activity against the TrkA enzyme using sequential chemical reactions. The targeted compounds were screened in vitro using an MTT assay against three cell lines, including HepG2, MCF-7, and K-562. Some of the screened compounds exhibited good antitumor activity, such as compound 6m, which showed more potent activity against the MCF-7 cell line, with an IC₅₀ of 19.1 μM, compared to 24.2 μM for 5-fluorouracil, a reference drug. Furthermore, cell cycle and apoptosis assays were performed to confirm the induction of cell cycle arrest in the G1 phase in addition to their potent antiproliferative effects. In addition, an enzyme inhibition assay was performed for all prepared compounds against the TrkA enzyme. Compounds 6b, 6i, 6j, and 6n exhibited the most preferable activity, with IC₅₀ values of 8.9, 8.9, 8.0, and 6.6 μM, respectively, compared to Sorafenib (IC₅₀ = 0.6 μM), serving as a control drug. Moreover, in silico computational studies, such as molecular docking and ADME predictions, were done to predict the ligand-protein interactions, physicochemical properties, and oral bioavailability of the proposed compounds.