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The prevalence and impact of helminthiasis on public health and animal production is a socio-economic problem in developing countries. Benzimidazole derivatives are known to possess diverse pharmacological activities, which include anthelmintic properties. However, the increasing resistance of helminths to current treatment has led to the continuous search for newer drugs. This study was thus designed to synthesise, characterise and determine the anthelmintic activity of new benzimidazole derivatives.
A series of 2-furanyl and 2-phenyl benzimidazoles were synthesised, through one-pot oxidative cyclo-condensation reaction of substituted o-phenylenediamines with furaldehyde and benzaldehyde derivatives via two-step processes, and heating at 25.0±1.0 oC. The liquid furanyl (which were freeze-dried prior to purification) and the solid phenyl products were purified by passing boiling n-hexane over them, and characterised by Mass Spectrometry (MS), 1H and 13C Nuclear Magnetic Resonance (NMR), Infra-red and Ultra-Violet spectroscopy. The anthelmintic activity against intestinal nematodes of cattle was determined in-vitro, utilising the egg hatch inhibitory assay at varying concentrations (12.5-100.0 g/L) in triplicate, with Albendazole as standard. The IC50 were calculated using probit analysis.
Forty benzimidazoles were synthesised of which thirty-one, including all the 2-phenyl compounds, were new. Typical of the 2-furanyl benzimidazoles was 5-fluoro-2-(5′-methylfuran-2′-yl)-1H-benzo[d]imidazole with a mass-to-charge ratio (m/z) of 216.0704 (calculated, 216.0699) obtained from high resolution-MS, corresponding to C12H9FN2O. Six resonances were observed on 1H NMR spectrum at δH 7.6, 7.4, 7.2, 7.1, 6.4 (representing aromatic protons) and 2.4 ppm (representing methyl protons). The 13C NMR spectrum showed nine resonance peaks assigned as δC 159.7, 157.9, 154.6, 144.6 to quarternary, 112.8, 110.7, 110.5, 108.8 to methine, and 13.5 ppm to methyl carbons. Characteristic Infra-red stretching vibrational frequencies at 3380, 3111, 2924, 1639, 1570, 1215 and 1145 cm-1 for N-Hamine, C-Haromatic, C-Haliphatic, C=N, C=Caromatic, C-O-Cether and C-Faromatic respectively, were seen. Ultra-violet maximum wavelenghts of absorptions were at 301, 255 and 213 nm, indicative of n→* and →* transitions. A representative of the 2-phenyl benzimidazoles was 2-(3′-(benzyloxy)-4′-methoxyphenyl)-5-nitro-1H-benzo[d]imidazole. High resolution-MS revealed a m/z of 375.1233 (calculated 375.1219), corresponding to C21H17N3O4. The
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1H NMR spectrum showed eleven resonances at δH 8.4, 8.1, 7.9, 7.8, 7.7, 7.5, 7.4, 7.3, 7.2, 5.2 and 3.8 ppm for aromatic, methylene and methoxy protons. Fourteen resonances, δC, comprising the quarternary (155.8, 151.6, 148.0, 142.5, 136.7, 121.2 ppm), methine (128.3, 127.8, 120.6, 117.7, 112.2, 111.9 ppm), methylene (70.1 ppm) and methoxy (55.7 ppm) carbons, were exhibited on 13C NMR spectrum. Infra-red stretching vibrations for N-Hamine, C-Haromatic, C-Haliphatic, C=Caromatic, N=Onitro and C-O-Cether were observed at 3325, 3072, 2931, 1600, 1338 and 1268 cm-1, respectively. The Ultra-violet spectrum, showed maximum absorptions indicating n→* and →* transitions, at 218, 230, 282 and 344 nm. Three of the new compounds showed potent inhibitory activity with 2-(2′-bromo-4′,5′-dimethoxyphenyl)-1H-benzo[d]imidazole been the most active (IC50=17.5 g/L) compared to Albendazole (IC50=11.4 g/L).
Thirty-one of forty characterised benzimidazoles were newly synthesised. Three of the benzimidazoles indicated promising anthelmintic properties and require further development into drugs as remedy for helminthiasis.
Keywords: o-Phenylenediamines, Benzimidazoles, Helminthiasis, Egg hatch
inhibitory assay.
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