Synthesis of Novel Pyrimidine Derivatives as Bioisosters of Nifedipine and In Vitro Evaluation of their Antihypertensive Activity

Abstract

3,4-dihydropyrimidin-2(1H) compounds have been attracted researchers to synthesize them via Beginilli reaction and evaluate their antihypertensive activities as bioisosters of nifedipine. The aim was to evaluate
the antihypertensive activities of new synthetic pyrimidine compounds compare with nifedipine. The new compounds were prepared from one pot reaction of thiourea (1), ethyl acetoacetate (2) and/or p-nitrobenzaldehyde, ptolualdehyde (3), respectively, in acid medium (HCl) yielding pyrimidine 4a-c which in turn were hydrolyzed to
carboxylic acid derivatives 5a-c which were chlorinated by SOCl2 to give acyl chlorides 6a-c; finally the latter
were reacted with some selected aromatic amines namely, aniline, p-anisidine and p-nitroanilin producing
amides 7a-c, 8a-c, and 9a-c, respectively. A total of 95 adult rats were divided into 7 groups and given the new
compounds and one group received nifedipine. Rats were anaesthetized and the blood pressure was measured
though the carotid artery by using of mercury manometer. Results showed that compound 7a has a better antihypertensive activity with insignificant difference compared to nifedipine, while 8a-c and 9a-c have significant difference as compared with nifedipine that indicated when aniline was used as an aromatic amine provides the
highest calcium blocking activity. In conclusion, the best antihypertensive active compounds were amides 7a-c,
8a-c and 9a-c. Better results were obtained especially when the benzene ring of amide is unsubstituted.