Abstract
A number of 5-aryl-1-methyl-4-nitroimidazoles 5a-f have been synthesized in good yields by the Suzuki coupling reaction between 5-chloro-1-methyl-4-nitroimidazole (3) and arylboronic acids 4a-f, aided by dichlorobis-(triphenylphosphine)palladium(II), K2CO3, and tetrabutylammonium bromide in water at 70-80 °C. Compounds 5a-f were characterized by elemental analysis, NMR and MS spectral data. On the basis of in vitro screening data, 5-(3-chlorophenyl)-1-methyl-4-nitro-1H-imidazole (5f) exhibited potent lethal activity against Entamoeba histolytica and Giardia intestinalis with IC50 = 1.47 µM/mL, a value lower by a factor of two than that of the standard drug, metronidazole. The boosted activity of 5f was not accompanied by any increased cytotoxicity. The rest of the series also exhibited potent antiparasitic activity with IC50 values in the 1.72-4.43 µM/mL range. The cytotoxicity of the derivatives 5c and 5e was increased compared to the precursor compound, metronidazole, although they remain non-cytotoxic at concentrations much higher than the antiparasitic concentration of the two derivatives.
Highlights
The imidazole nucleus occurs naturally in L-histidine, histamine (a vasodelator hormone), thiamine (vitamin B1), and in several other biomolecules [1,2,3,4]
The imidazole nucleus occurs naturally in L-histidine, histamine, thiamine, and in several other biomolecules [1,2,3,4]
This step led to a mixture of 5a and its isomeric 1-methyl-4-aryl-5-nitroimidazole 7A, the isolation of which required extra separation and purification efforts
Summary
The imidazole nucleus occurs naturally in L-histidine, histamine (a vasodelator hormone), thiamine (vitamin B1), and in several other biomolecules [1,2,3,4]. A number of synthetic 5-(substituted azolyl)-1-methyl-4-nitroimidazoles were reported to exhibit anti-parasitic activity [20,21,22]. Synthesis of 5-aryl-1-methyl-4-nitroimidazoles 5a-f via Suzuki coupling. Compared to the multistep synthetic route noted above, the direct Suzuki coupling reaction provides a more convenient and efficient route for the preparation of 5-aryl-1-methyl-4-nitroimidazoles 5a-f.
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