Design, Synthesis, and Anticancer Activity of Novel Methoxycyclohexyl Nicotinamides

• Published in: Russian journal of organic chemistry Vol. 60; no. 1; pp. 173 - 184
• Main Authors: Mulik, B. M., Srivastava, N., Pendharkar, D., Guin, M.
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 2024; Springer Nature B.V
• Subjects: Anticancer properties; Cancer; Chemistry; Chemistry and Materials Science; Heterocyclic compounds; Kinases; Leukemia; Nicotinamide; NMR; Nuclear magnetic resonance; Organic Chemistry; Side effects; Synthesis; Tyrosine; tyrosine kinase inhibitors; chronic myeloid leukemia; anticancer activity; ADME
• ISSN: 1070-4280; 1608-3393
• DOI: 10.1134/S1070428024010226

Over the past decade, the molecular targeted therapies have been found beneficial. These therapies utilize small chemical molecules which block the growth and spread of cancer by interfering with specific proteins involved in tumor growth and progression. The molecular targeted anticancer therapies use chemically cytotoxic molecules with a defined biological target. Tyrosine kinase inhibitors (TKIs) can target cancer cells without affecting normal cells, thus reducing the risk of side effects. A wealth of choices exists for first-line treatment selection, including the first-generation TKI imatinib and the second-generation TKIs bosutinib, dasatinib, and nilotinib. Asciminib was reported as tyrosine kinase inhibitor and was later approved by the US FDA. We have designed and synthesized novel methoxycyclohexyl nicotinamide analogues of asciminib. All synthesized compounds were characterized by
1
H and
13
C NMR and LCMS data. Biological evaluation was carried out in vitro by Resazurin assay against two cancer cell lines, K562 (human chronic myelogenous leukemia cell line) and MV411 (human acute myeloid leukemia cell line). ADME and toxicity prediction of the novel heterocyclic compounds was performed by Swiss ADME, AdmetSAR, and Molinspiration. The designed compounds showed good docking scores. However, the synthesized compounds exhibited moderate activity on the leukemia cell lines.