Background: Cancer was credited as the second leading cause to global death rate with estimated toll of deaths more than 18 million. Though many anticancer agents are available in the market, there is an essential need to explore novel drug candidates for cancer treatment due to the various adverse effects associated with the current anticancer agents. Pyrimidine scaffold is a ubiquitous heterocyclic system present in important anticancer agents. Current investigation aims to find the newer class of anticancer lead molecules with pyrimidine as the central pharmacophore. Objective: Primary objective of the current research is to evaluate the anti-cancer potential of the novel class of carboxamide functionality tethered pyrimidine derivatives against six different cancer cell lines.
Method: Current research designed and synthesized a novel class of pyrimidine based molecular hybrids of aryl amines via carboxamide linkage. The targeted pyrimidine carboxamide derivative synthesized from a multistep process. Initially, Ethyl 4-hydroxy-2-(methylthio) pyrimidine-5-carboxylate (3) was synthesized from the condensation of S -methylisothiourea hemisulfate (1) and diethyl ethoxymethylenemalonate (2) in the basic medium followed by the acid work up. The pyrimidine carboxylate synthesized hydrolyzed to its acidic form 4-hydroxy-2-(methylthio) pyrimidine-5-carboxylic acid (4), that tethered with various aryl amines (a-o) through amide link with the help of coupling agent DCC/DMAP to yield final compounds 5a-5o. All the synthesized derivatives were characterized by IR, 1HNMR and MASS spectral methods and anti-cancer activity evaluated by employing MTT assay for six cancer cell lines and one normal human cell line.
Results: All the synthesized compounds were screened for anti-cancer activity against six cancer cell lines including A 549 (lung), DU 145 (prostate), HT 29 (colon), MCF-7 (breast), SiHA (cervical), B16F10 (mouse skin melanoma) and one normal human fibroblast cell lines. All the compounds displayed decent cytotoxicity profile when compared with the standard drug doxorubicin. Among the synthesized compounds (5a to 5o) tested, four compounds, 5f, 5d, and 5l have demonstrated excellent cytotoxicity against selected cancer cell lines.
Conclusion: Comparatively, most of the compounds displayed decent cytotoxic potential relative to the standard drug doxorubicin. Further investigations are needed to establish the detailed mechanism of action of the developed novel pyrimidine carboxamide derivatives.
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