Antiamoebic and Toxicity Studies of a Carbamic Acid Derivative and Its Therapeutic Effect in a Hamster Model of Hepatic Amoebiasis

Abstract

Amoebiasis is an important public health problem in developing countries. Entamoeba histolytica, the causative agent of amoebiasis, may develop resistance to nitroimidazoles, a group of drugs considered to be the most effective against this parasitic disease. Therefore, research on new drugs for the treatment of this common infection still constitutes an important therapeutic demand. In the present study we determined the effects of a carbamate derivative, ethyl 4-chlorophenylcarbamate (C4), on trophozoites of E. histolytica strain HM-1: IMSS. C4 was subject to various toxicity tests, including the determination of mutagenicity for bacterial DNA and changes in the enzymatic activities of eukaryotic cells. Genotoxicity studies were performed by the mutagenicity Ames test (plate incorporation and preincubation methods) with Salmonella enterica serovar Typhimurium, with or without metabolic activation produced by the S9 fraction of rat liver. C4 toxicity studies were performed by measuring enzymatic activity in eukaryotic cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-formazan test with Fischer 344 rat hepatocytes. C4 did not induce either frameshift mutations in S. enterica serovar Typhimurium TA97 or TA98 or base pair substitutions in strains TA100 and TA102. The compound was not toxic for cultured rat hepatic cells. Trophozoites treated with 100 g of C4 per ml were inhibited 97.88% at 48 h of culture; moreover, damage to the amoebae was also confirmed by electron microscopy. The antiamoebic activity of C4 was evaluated by using an in vivo model of amoebic liver abscess in hamsters. Doses of 75 and 100 mg/100 g of body weight reduced the extent of the amoebic liver abscess by 84 and 94%, respectively. These results justify further studies to clearly validate whether C4 is a new suitable antiamoebic drug.

Parasitic diarrheal disease: drug development and targets

“…It is an organism implicated in both diarrheal disease and invasive disease such as liver abscesses. Metronidazole ( 14 ) is the first line medication used against the infection but long-term uses produce several side effects in patients (Ordaz-Pichardo et al, 2005 ). It is potentially carcinogenic to humans because it is genotoxic to human cells (Bendesky et al, 2002 ).…”

Metronidazole hydrazone conjugates: Design, synthesis, antiamoebic and molecular docking studies

“…Entamoeba histolytica MTT-Assay Thioredoxin reductase In order to explore the possible antiamoebic potential of newly synthesized metronidazole-hydrazone conjugates (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), all the compounds were screened against HM1: IMSS strain of E. histolytica by microdilution method 15 and the results were compared with the most widely used antiamoebic drug MNZ that had 50% inhibitory concentration (IC 50 ) 1.81 μM in our experiments. All the title compounds (2-13) exhibited better IC 50 values (0.20-7.12 μM) than the compound 1 (IC 50 = 11.48 μM).…”

“…5 Metronidazole (MNZ), tinidazole (TZ) and ornidazole (OZ) (Figure 1) are the widely used medicament for the treatment of protozoal infections, in which MNZ is the drug of choice for the treatment of amoebiasis, but long term use causes several side effects. 6 Although, it is mutagenic in bacteria, carcinogenic to rodents and genotoxic to human cells. 7 However, due to inadequate epidemiological evidence, it is not considered as a risk factor of cancer in humans.…”

“…In this paper, we herein report the synthesis, antiamoebic activity, molecular docking and lipophilic studies of metronidazole hydrazone conjugates ( Figure 4). Metronidazole hydrazone conjugates (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) were synthesized and screened in vitro for antiamoebic activity against HM1: IMSS strain of Entamoeba histolytica. Six compounds were found to be better inhibitors of E. histolytica than the reference drug metronidazole.…”

Synthesis, characterization and antiamoebic activity of chalcones bearing N-substituted ethanamine tail

“…The spread of the infection is accelerated by poor sanitation. The treatment is usually done by nitroimidazoles such as metronidazole (MNZ) and tinidazole but they have shown several side effects [2]. MNZ is known to be carcinogenic in rodents and some major side effects such as irritation of the gastric mucus lining, spermatozoid damage, convulsions, central nervous system disorders, blood in urine [3e7].…”