Synthesis and cytotoxic activity of new pyrazolo[1,5-a]pyrimidines and determination of pyrimidine regiospecific ring formation with 2D NMR

Abstract

Novel pyrazolo [1,5-a]pyrimidines (9a, 9b, and 10a-c) were synthesized in high and efficient yields. Their pathway involves the formation of N,S-ketene derivatives (7a and 7b) that reacted with hydrazine hydrate to get the key intermediate aminopyrazolo derivatives (8a and 8b). These aminopyrazoles were further reacted with either acetylacetoneor β-ketoesters resulting in the targeted pyrazolopyrimidines (9a, 9b, and 10a-c). All prepared compounds were fully characterized by spectral methods and the cyclization of 10a-d was proved by 2D NMR such as HMBC, HSQC and NOESY. The targeted pyrazolopyrimidines were subjected to in vitro anticancer screening and all of them showed promising cytotoxic activity when compared to doxorubicin. Compound 10d was the most active with IC50= 1.98, 2.20 and 2.61µM against MCF-7, BT474 and A549 cancer cell lines.

Imidazo- and pyrazolopyrimidine scaffolds as anticancer agents

“…This may be attributed to the thiazole moiety. In addition 115d was more reactive than 115b which could be related to the phenyl ring, it showed IC50 1.98 μM, 2.20 μM, and 2.61 μM against MCF-7, BT474, and A-549 cell lines, respectively 63 Ali et al, 67 followed a specified synthetic route to produce the desired derivatives by first nucleophilic addition reaction of phenyl isothiocyanate (145) with various derivatives containing active methylene group either as cyanoacetamide, or malononitrile. The produced compound underwent cyclization by fusion with hydrazine hydrate.…”

“…In addition, Abdelal et al 63 achieved the synthesis of pyrazolopyrimidine-benzothiazole / benzimidazole hybrids 114a,b, and 115a-d by refluxing a mixture of the appropriate aminopyrazole, and acetylacetone, ethyl acetoacetate, or ethyl-3-oxo-3-phenylpropanoate in glacial acetic acid. Their anticancer activities were tested against MCF-7, BT474, and A-549 cell lines; compounds 115b, and 115d revealed the highest activities.…”