Integration of Hybridization Strategies in Pyridine-Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights

Annually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial. Small molecules possessing pyridine and urea moieties have been reported in many of the currently available anticancer agents, especially VEGFR2 inhibitors. With this in mind, a rational design approach was employed to create hybrid small molecules combining urea and pyridine. These synthesized compounds underwent in vitro testing against breast and colon cancer cell lines, revealing potent submicromolar anticancer activity. Compound 8a, specifically, exhibited an impressive GI(50) value of 0.06 & mu;M against the MCF7 cancer cell line, while compound 8h displayed the highest cytotoxic activity against the HCT116 cell line, with a GI(50) of 0.33 & PLUSMN; 0.042 & mu;M. Notably, compounds 8a, 8h, and 8i demonstrated excellent safety profiles when tested on normal cells. Molecular docking, dynamic studies, and free energy calculations were employed to validate the affinity of these compounds as VEGFR2 inhibitors.

Automated summary

Each year, millions of new cancer cases are reported, resulting in millions of deaths worldwide. Breast and colon cancers are the most commonly detected variations. To address this increase, the development of innovative therapies is crucial. Small molecules containing pyridine and urea have been found in many anticancer agents, particularly VEGFR2 inhibitors. Hybrid small molecules combining urea and pyridine were designed and tested against breast and colon cancer cell lines, showing potent anticancer activity. Compound 8a displayed a remarkable GI(50) value of 0.06 μM against the MCF7 cancer cell line, while compound 8h exhibited the highest cytotoxic activity against the HCT116 cell line, with a GI(50) of 0.33 ± 0.042 μM. Importantly, compounds 8a, 8h, and 8i demonstrated excellent safety profiles on normal cells. Molecular docking, dynamic studies, and free energy calculations confirmed the affinity of these compounds as VEGFR2 inhibitors.