Abstract 5742: Synthesis of substituted benzimidazole tetrahydropyridines as anti-breast cancer agents

Abstract Breast cancer is the most common type of cancer worldwide. In 2023, the World Health Organization (WHO) reported that 2.3 million women were diagnosed with breast cancer, leading to 670, 000 deaths. Furthermore, the incidence rates of breast cancer have been rising at 3% each year. Overexpression of COX-2 in breast cancer tissues is associated with poor prognosis, including higher tumor grade, increased metastatic potential, and resistance to therapy. Selective COX-2 inhibitors have demonstrated potential in reducing tumor growth in preclinical and some clinical studies. These inhibitors may also enhance the effectiveness of chemotherapy and radiotherapy. The benzimidazole nucleus is a valuable subunit for the development of pharmaceuticals and biologically relevant molecules. Tetrahydropyridine (THP)analogs are compounds with diverse biological activities, including analgesics, anti-inflammatory agents, and chemotherapeutic agents. Our previous research findings indicated that the THP derivatives exhibited COX-2 inhibition and demonstrated anti-inflammatory effects in rat paw edema assays. The pharmacological activities of THP derivatives depend on the nature of the substituents in the THP ring system. The incorporation of a benzimidazole moiety may enhance the biological activity of these THP derivatives. Thus, the design and synthesis of novel series of benzimidazole-THP derivatives with potential anticancer and anti-inflammatory activities were initiated. In the current investigation, we synthesized numerous analogs maintaining the N-(5-(1H-benzo[d]imidazol-2-yl)-3, 6-dihydropyridin-1(2H)-yl)benzamide/benzene sulfonamide having modifications on the phenyl ring. We expect that these structural modifications would affect the compounds electron density, lipophilicity and the compounds steric configurations. The starting material 2-(pyridin-3-yl)-1H-benzo[d]imidazole was obtained by the reaction of nicotinic acid, 1, 2-phenyldiamine and polyphosphoric acid by stirring in an oil bath at 180o C for 2 h. N-Amination of substituted 2-(pyridin-3-yl)-1H-benzo[d]imidazole by an aminating agent O-(mesitylsulfonyl)hydroxylamine (MSH), followed by ylide formation and further reduction yielded the desired substituted N-(5-(1H-benzo[d]imidazol-2-yl)-3, 6-dihydropyridin-1(2H)-yl)benzamide derivatives. Final compounds were analyzed via NMR spectroscopy, IR and elemental analysis. The analogs were evaluated for through docking studies. Two products showed significant anti-inflammatory and anti-breast cancer activities. Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Absera W. Haile, Suresh Eyunni. Synthesis of substituted benzimidazole tetrahydropyridines as anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5742.