title: New synthesis and antiparasitic activity of model 5-aryl-1-methyl-4-nitroimidazoles.
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), K(2)CO(3, )and tetrabutylammonium bromide in water at 70-80 degrees 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 IC(50) = 1.47 microM/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 IC(50 ) values in the 1.72-4.43 microM/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.
authors.affiliation: Chemistry Department, Faculty of Science, University of Jordan, Amman 11942, Jordan. h.saadeh@ju.edu.jo
authors.forename: Haythem A
authors.initials: HA
authors.lastname: Saadeh
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Mosleh
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: El-Abadelah
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D004748:Entamoeba histolytica / Q000187:drug effects; D016829:Giardia lamblia / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000977:Antiparasitic Agents; D009593:Nitroimidazoles; C052587:4-nitroimidazole
references.citation: Molecules. 2009 Apr 09;14(4):1483-94
references.pmid: 19384280
references.citation: Trans R Soc Trop Med Hyg. 1991 Jan-Feb;85(1):67-9
references.pmid: 2068765
references.citation: Pharm Res. 1996 Sep;13(9):1401-5
references.pmid: 8893282
references.citation: Bioorg Med Chem. 1997 Mar;5(3):591-9
references.pmid: 9113337
references.citation: Curr Med Chem. 2006;13(1):1-23
references.pmid: 16457636
references.citation: J Antimicrob Chemother. 1980 Sep;6(5):577-93
references.pmid: 6106010
references.citation: Angew Chem Int Ed Engl. 2001 Dec 17;40(24):4544-4568
references.pmid: 12404358
references.citation: Chem Rev. 2002 May;102(5):1359-470
references.pmid: 11996540
references.citation: J Med Chem. 1988 Feb;31(2):323-9
references.pmid: 3339605
references.citation: Reg Anesth Pain Med. 2003 May-Jun;28(3):248-52
references.pmid: 12772145
references.citation: Clin Microbiol Rev. 2002 Jul;15(3):329-41
references.pmid: 12097242
references.citation: Cytobios. 2001;105(409):83-90
references.pmid: 11393774
references.citation: Mini Rev Med Chem. 2005 Apr;5(4):409-24
references.pmid: 15853629
references.citation: Angew Chem Int Ed Engl. 2000 Jan;39(1):165-168
references.pmid: 10649362
references.citation: Drugs. 1978 Nov;16(5):387-417
references.pmid: 363399
references.citation: Drugs. 1997 Nov;54(5):679-708
references.pmid: 9360057
references.citation: J Antimicrob Chemother. 1986 Mar;17(3):269-79
references.pmid: 3516967
references.citation: Infect Immun. 1994 Dec;62(12):5397-403
references.pmid: 7960119
references.citation: Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):673-80
references.pmid: 8948352