New pyrimidine-5-carbonitrile derivatives as EGFR inhibitors with anticancer and apoptotic activities: design, molecular modeling and synthesis

Abstract

In connection with our efforts on the development of new anticancer agents, herein we report the design and synthesis of new small pyrimidine-5-carbonitrile based derivatives. The target pyrimidines were evaluated...

Design, synthesis, in silico studies, and biological evaluation of novel pyrimidine-5-carbonitrile derivatives as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

“…First, the starting material 2mercapto-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitril 1 was obtained in a good yield by the cyclocondensation of benzaldehyde with ethyl cyanoacetate and thiourea in alkaline media according to the reported method. [21][22][23] The derivative 1 was subjected to the alkylation with an equivalent amount of methyl iodide in 10% alcoholic KOH to afforded 2-(methylthio)-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile 2. Thus, reuxing of compound 2 with phosphorus oxychloride afforded the corresponding the key intermediate 3.…”

“…Condensation of the keton derivatives 5 and 6 with the appropriate acid hydrazides 10a-g (obtained according to the reported procedures) 16,23,24 at heating and reuxing temperature in absolute ethanol containing catalytic amount of glacial acetic acid afforded the respective hydrazono compounds 11a-e and 12a-g, respectively (Scheme 3).…”

Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFRWT/COX-2 inhibitors with docking studies

“…Two members of the new series 4e & 4f disclosed potent anticancer activity against all tested cell line, as a result 4e & 4f have been undergo further anticancer screening in ve-dose assay [0.01, 0.1, 1, 10, and 100 mM] by NCI. Moreover, the safety prole of 4e & 4f at normal cells were evaluated [6,7].…”

“…[3][4][5] EGFR has been identied as a crucial regulator of numerous biological processes, including cell cycle progression, apoptosis inhibition, and tumor cell motility. 6 Thus, suppression of the EGFR protein kinase is regarded as a promising anti-cancer treatment strategy for many types of cancer. 7 There are two major ways to stop the oncogenic EGFR tyrosine kinase activity.…”

“…2). 6,21,22 Also, pyrimidine-5-carbonitriles have also gotten recognition for their anti-inammatory and analgesic activities through COX isoenzymes inhibition (Fig. 2).…”