Utilization of a Propenone Derivative in the Synthesis of Some New Cytotoxic Heterocyclic Compounds

Abstract

New diaryl-substituted pyridine, pyrimidine, pyrazole, and isoxazole derivatives bearing biphenyl-4-yl and 4-(dimethylamino)phenyl substituents have been prepared by the reaction of 1-(1,1′-biphenyl-4-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1-one with different nitrogen nucleophiles such as urea, thiourea, guanidine hydrochloride, semicarbazide hydrochloride, thiosemicarbazide, and hydroxylamine hydrochloride. Nicotinonitrile derivative has been synthesized by one-pot reaction of 4-acetylbiphenyl, 4-(dimethylamino)benzaldehyde, and malononitrile in the presence of ammonium acetate under microwave irradiation, and subsequent treatment with hydrazine hydrate gave 4,6-diaryl-1H-pyrazolo[3,4-b]pyridin-3-amine. The behavior of 4,6-diarylpyrimidin-2-amine toward carbon electrophiles has been investigated by reacting it with p-toluenesulfonyl chloride, acetyl chloride, ethyl acetoacetate, ethyl cyanoacetate, and nitrous acid to afford the corresponding N-substituted derivatives. 3,5-Diaryl-4,5-dihydro-1H-pyrazole-1-carboxamide reacted with p-toluenesulfonyl chloride and phenylhydrazine to produceN-tosyl carboxamide and carbohydrazonamide derivatives, respectively. Treatment of analogous pyrazole-1-carbothioamide with phenyl isothiocyanate, p-toluenesulfonyl chloride, and chloroacetyl chloride affordedN-(phenylcarbamothioyl), N-tosyl, and aminoacetamide derivatives, respectively. All the synthesized compounds were characterized by1H NMR, IR, and mass spectra and elemental analyses. Some of the newly synthesized compounds were evaluated for theirin vitro cytotoxic activity against HePG-2 and MCF-7 cell lines. 4-(1,1′-Biphenyl-4-yl)-6-[4-(dimethylamino)phenyl]-5,6-dihydropyrimidine-2(1H)-thione and 4-[5-(1,1′-biphenyl-4-yl)-4,5-dihydro-1,2-oxazol-3-yl]-N,N-dimethylaniline displayed a promising growth inhibitory effect toward the two cell lines in comparison with the standard drug doxorubicin.