Synthesis of some heterocyclic compounds with anticipated biological activity.

Abstract

First part: 1-([1,1'-biphenyl]-4-yl)-3-(4-(dimethylamino)phen-yl)prop-2-en-1-one (3) was synthesized by conventional method, compound 3 was treated with different nitrogen nucleophiles such as urea, thiourea, guanidine hydrochloride, semicarbazide hydro-chloride, thiosemicarbazide, and hydroxylamine hydrochloride to produce the corresponding pyrimidines 6-8, pyrazolocarboxamide 9, pyrazolocarbothioamide 10 and the isoxazole 11 derivatives, respectively. Meanwhile, compound 3 was allowed to react with malononitrile, ethyl acetoacetate and acetyl acetone to produce compounds 12-14, respectively. Nicotinonitrile derivative 4 has been synthesized by one pot reaction of 4-acetylbiphenyl (1), 4-(dimethylamino) benzaldehyde (2), and malononitrile in the presence of ammonium acetate under microwave irradiation, which on reaction with hydrazine hydrate afforded the pyrazolopyridine derivative 5. Reaction of pyrimidine 8 with p-toluenesulfonyl chloride, acetyl chloride, ethyl acetoacetate and ethyl cyanoacetate gave compounds 15, 16, 18 and 19, respectively. On the other hand, when the pyrazolocarboxamide 9 was allowed to react with p-toluenesulfonyl chloride and/or phenyl hydrazine compounds 20 and 21 were obtained respectively. Reaction of compound 10 with phenyl isothiocyanate, p-toluenesulfonyl chloride and/or chloroacetyl chloride afforded the pyrazole derivatives 22, 23 and the dimer compound 24, respect-tively. The newly synthesized compounds were characterized by the spectroscopic tools IR, 1H-NMR, mass spectra and elemental analyses. Some of the newly synthesized compounds were evaluated for their in vitro cytotoxic activity against HePG-2 and MCF-7 cell lines. 4-([1,1'-biphenyl]-4-yl)-6-(4-(dimethylamino)phenyl )-5,6-dihydro-pyrimidine-2(1H)-thione (7) and 4-(5-([1,1'-biphenyl]-4-yl)-4,5-dihydroisoxazol-3-yl)-N,N-dimethylaniline (11) displayed a promising growth inhibitory effect toward the two cell lines in comparison with the standard drug doxorubicin.

Second part: the starting nicotinonitrile derivative 25 was prepared via one pot reaction of acetophenone, anisaldehyde, malononitrile and ammonium acetate under microwave irradiation. The reactivity of nicotinonitrile 25 was studied towards different reagents by its reaction with formamide, thiourea, acetic anhydride and phthalic anhydride under optimized conditions to give compounds 26, 27, 29, and 32, respectively. The pyridine thiourea 27 was also prepared alternatively via reaction of nicotinonitrile 25 with ammonium thiocyanate. Its reaction with hydrazine hydrate afforded the pyridine derivative 28. The monoacetylated product 29 when subjected to react with o-phenylene diamine and/or hydrazine hydrate gave compounds 30 and 31, respectively. Compound 25 was allowed to react with malononitrile, phenacyl bromide, ethyl bromoacetate, p-toluenesulphonyl chloride, chloroacetyl chloride, benzoyl chloride, diethyl malonate, ethyl cyano acetate to give compounds 33-39 and 42, respectively. Structure of compound 39 was further supported by its reaction with hydrazine hydrate and/or 4-nitroaniline to give compounds 40 and 41, respectively. The reactivity of nicotinonitrile 25 was also studied towards a variety of reagents such as cyanoacetic acid, anisaldehyde, phenyl isocyanate, triethyl orthoformate, sodium nitrite/HCl/aniline, isa-tine and/or 1,3-dibromopropane to give compounds 43, 45-49, respectively. The newly synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR, mass spectral data and elemental analysis. Some newly synthesized compounds have been screened in vitro anti-microbial against different strains of bacteria and fungi and also they were evaluated for their in vitro cytotoxic effect against a panel of several cell lines (human tumor). The structure activity relationship (SAR) has also been studied.