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.