N-Sübstitüe Amidin Grubu Taşıyan Benzimidazol Türevi Bileşiklerin Sentez, Yapı Aydınlatmaları ve Antimikrobiyal Etkileri Üzerinde Çalışmalar.
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Date
2007
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Sağlık Bilimleri Enstitüsü
Abstract
In this study, at the first step, 4-amino-3-nitrobenzonitrile was converted to imidate ester by using anhydrous ethanol with saturated dry HCl gas, followed by the unstable ester was immediately converted to 4-amino-3-nitrobenzamidine (1) with passing through NH3 gas in ethanol. The Pd/C catalyzed reduction of 1 gave 3,4-diaminobenzamidin (2). Benzimidazol cyclization was performed by heating 2 with the 3,4-dinitrobenzoic acid in polyphosphoric acid, and 2-(3,4-dinitrophenyl)-benzimidazole 5-carboxamidine was obtained (3). Reduction of both nitro group yielded 2-(3,4-diaminophenyl) benzimidazole-5-carboxamidine (4). Condensation of 4-chlorophenol with 2-fluorobenzaldehyde, 4-fluorobenzaldehyde, 2,5-difluoro-benzaldehyde; and 3,4-dimetoxyphenol with 4-fluorobenzaldehyde yielded the corresponding substitue-phenyloxybenzaldehydes (5-8). The final compounds (9-26) were obtained by condensation of 2-(3,4-diaminophenyl)-benzimidazole-5(6)-carboxamidine (4) with Na2S2O5 adduct of 5-8 and commercial arylaldehydes in DMF. A series of novel 18 final compounds (with 2 novel and 6 known intermediates) was prepared in this study. The purity of these compounds was checked with their melting points, TLC and tR retentation times in reverse phase HPLC. The chemical structures of the compounds were elucidated with their 1H-NMR, 13C-NMR, 19F-NMR, 2D-COSY, 2D-HSQC spectrum, Mass (ESI+) spectral data and their elemantel analysis. The synthesized compounds (9-26) were screened for their in vitro activity against four parasitic protozoa, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum. The medium-throughput screening method was used to test the compouds at two concentrations, 0.81 ?M and 4.85 ?M, respectively. According to medium-throughput screening results, all compounds have significant inhibitory activity against P. falciparum and thirteen of them have remarkable inhibitory activity against T. b. rhodesiense at low concentration, its IC50 values were determined. On the other hand, none of these compounds displayed appreciable inhibitory activity against T. cruzi and L. donovani, therefore not further investigated to determine their IC50 values. The in vitro antifungal activity of the synthesized compounds against Candida albicans and Candida krusei is evaluated with Macrodilution Techniques. The cytotoxic potentials of these compounds on mammalian (rat skeletal muscle myoblast, L6) cells were also assessed and compared to that of podophyllotoxin. Compound 10, 17 and 24, with IC50 values of 0.041, 0.06 and 0.036 ?g/ml respectively, are the most active monocation against T. b. rhodesiense. The most potent antiplasmodial compounds, 9, 10, 17, showed IC50 values as 0.007, 0.010 and 0.008 ?g/ml respectively. Compound 25 (IC50 = 0.78 ?g/ml) and 12 (IC50 = 1.56 ?g/ml) were highly effective against C. albicans. Compounds 13 and 24 exhibited the best antifungal activity against C. krusei with IC50 value of 6.25 ?g/ml. In general, there was good selectivity for the parasitic organisms by synthesized compounds (9-26) as judged from their cellulary cytotoxicity. In order to explain the quantitative structure activity relationship between the synthesized compounds and their inhibitory activities against the selected protozoa and fungi, several parameters have been used. The best correlation was found with Log P values of the synthesized compounds against T. b. rhodesiense.
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Keywords
Antifungal aktivite, Antifungal activity, Antiprotozoal ajanlar, Antiprotozoal agents, Benzimidazol türevleri, Benzimidazole derivatives, Yapı aktivite ilişkisi, Structure activity relationship