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Abstract

The potential active pharmaceutical ingredient (API), N-[4-(2,4-Dimethylphenyl)-2-thiazolyl]-4-pyridinecarboxamide (6) is a cancer cell metabolism mitosis inhibitor via the Nek2 and Hec1 enzymes. The three-step synthesis starts with the bromination of 1-(2,4-dimethylphenyl)ethan-1-one (1) using CuBr2 to produce 2-bromo-1-(2,4-dimethylphenyl)ethan-1-one (2) with a yield of 90%.[i],[ii],[iii] Followed by Hantzsch thiazol ring synthesis as (2) reacts with thiourea (3) and, resulting in 4-(2,4-dimethylphenyl)thiazol-2-amine (4)[iv] in 80% yield. Finally, isonicotinoyl chloride hydrochloride (5) and (4) reacted to form the amide (6).[v],[vi],[vii],[viii],[ix],[x] Characterization of the final product was determined by HPLC, GCMS, 1H-NMR, FTIR, and mp with a crude yield of 60%.

[i] Sharley, J. S., Pérez, A. M. C., Ferri, E. E., Miranda, A. F., & Baxendale, I. R. (2016). α, β-Unsaturated ketones via copper (II) bromide mediated oxidation. Tetrahedron, 72(22), 2947-2954. https://www.sciencedirect.com/science/article/pii/S0040402016302654 [accessed June 15, 2023]

[ii] Ye, Z., Liu, C., Zou, F., Cai, Y., Chen, B., Zou, Y., ... & Qian, H. (2020). Discovery of novel potent GPR40 agonists containing imidazo [1, 2-a] pyridine core as antidiabetic agents. Bioorganic & Medicinal Chemistry, 28(13), 115574. https://www.sciencedirect.com/science/article/pii/S0968089620304041 [accessed June 15, 2023]

[iii] Wang, W., Han, J., Sun, J., & Liu, Y. (2017). CuBr-Catalyzed aerobic decarboxylative cycloaddition for the synthesis of indolizines under solvent-free conditions. The Journal of Organic Chemistry, 82(6), 2835-2842. https://pubs.acs.org/doi/full/10.1021/acs.joc.6b0245 [accessed June 15, 2023]

[iv] Petrou, A., Fesatidou, M., & Geronikaki, A. (2021). Thiazole ring—A biologically active scaffold. Molecules, 26(11), 3166. https://www.mdpi.com/1420-3049/26/11/3166 [accessed June 15, 2023]

[v] Sharma, M., Mangas-Sanchez, J., France, S. P., Aleku, G. A., Montgomery, S. L., Ramsden, J. I., ... & Grogan, G. (2018). A mechanism for reductive amination catalyzed by fungal reductive aminases. ACS Catalysis, 8(12), 11534-11541. https://pubs.acs.org/doi/full/10.1021/acscatal.8b03491?casa_token=r9ejB0_R2w0AAAAA%3AmjHGcFz4XCABP5dIS-s-1e-l3Wc1_3eEjd1OFwkFnUrAwmsexFY-P8haHDcxTbrHH9dtv380T3Sbgw8V [accessed June 15, 2023]

[vi] Srivastava, R. S., & Nicholas, K. M. (1997). On the mechanism of allylic amination catalyzed by iron salts. Journal of the American Chemical Society, 119(14), 3302-3310. https://pubs.acs.org/doi/pdf/10.1021/ja964006t [accessed June 15, 2023]

[vii] Qiu, X. L., Li, G., Wu, G., Zhu, J., Zhou, L., Chen, P. L., ... & Lee, W. H. (2009). Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues. Journal of medicinal chemistry, 52(6), 1757-1767. https://pubs.acs.org/doi/full/10.1021/jm8015969 [accessed June 15, 2023]

[viii]Sherr, C. J. (2000). The Pezcoller lecture: cancer cell cycles revisited. Cancer research, 60(14), 3689-3695. [accessed June 19, 2023]

[ix] Henriques, A. C., Ribeiro, D., Pedrosa, J., Sarmento, B., Silva, P. M., & Bousbaa, H. (2019). Mitosis inhibitors in anticancer therapy: When blocking the exit becomes a solution. Cancer letters, 440, 64-81. [accessed June 19, 2023]

[x] DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016 May 27;2(5):e1600200. doi: 10.1126/sciadv.1600200. PMID: 27386546; PMCID: PMC4928883.

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