Lilián Yépez-Mulia

Synthesis, antiprotozoal and anticancer activity of substituted 2-trifluoromethyl- and 2-pentafluoroethylbenzimidazoles.

The synthesis of several halogenated benzimidazoles substituted in position 2 with trifluoromethyl, pentafluoroethyl and 2-thioethylaminodimethyl group is reported. Antiprotozoal and anticancer activity of series of newly synthesized and previously obtained compounds was studied. All of tested bezimidazoles showed remarkable antiprotozoal activity against Giardia intestinalis, Entamoeba histolytica and Trichomonas vaginalis. Of the studied collection of halogenated benzimidazoles the most anticancer-active was the 5,6-dichloro-2-pentafluoroethyl compound, particularly against breast and prostate cancer cell lines.

Synthesis and biological activity of 2-(trifluoromethyl)-1H-benzimidazole derivatives against some protozoa and Trichinella spiralis

A series of 2-(trifluoromethyl)-1H-benzimidazole derivatives (1a-1i) were synthesized via Phillips cyclocondensation of a substituted 1,2-phenylenediamine and trifluoroacetic acid. The synthesized compounds were evaluated in vitro against various protozoan parasites: Giardia intestinalis, Entamoeba histolytica, Trichomonas vaginalis and Leishmania mexicana, and they showed nanomolar activities against the first three protozoa tested. The compounds were also tested in vitro and in vivo against the nematode Trichinella spiralis. Compounds 1b, 1c and 1e had the most desirable in vitro antiparasitic profile against all parasites studied. In the in vivo model against T. spiralis, compounds 1b and 1e showed good activity against the adult phase at 75 mg/Kg. However, against the muscle larvae stage, only compound 1f exhibited in vivo antiparasitic efficacy.

Synthesis and antiprotozoal activity of novel 1-methylbenzimidazole derivatives.

In this paper are reported the synthesis and antiprotozoal activity in vitro of 24 1-methylbenzimidazole derivatives (13-36) substituted at position 2 with aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, ethoxycarbonyl, 1-hydroxyethyl and acetyl groups, some of them with chlorine atoms at the benzenoid ring. Compounds 13-36 were more active than metronidazole, the choice drug against Giardia intestinalis and most of them against Trichomonas vaginalis. The most active group of compounds for both parasites was that with a 2-ethoxycarbonyl group (16, 22, 28, 34), independently of the substitution pattern at the benzenoid ring.

Giardia duodenalis: analysis of secreted proteases upon trophozoite-epithelial cell interaction in vitro

Protease secretion by Giardia duodenalis trophozoites upon interaction with epithelial cells and its association with the parasite adhesion was studied in co-cultures of parasites with IEC6 epithelial cell monolayers in the presence or absence of protease inhibitors. Proteolytic activity in supernatants from trophozoites was enhanced when they were co-cultured with IEC6 cells. This activity was strongly inhibited by pre-incubation of live trophozoites with E-64 and TPCK and a concomitant inhibition of parasite adhesion to IEC6 cells was observed. These data suggest that trophozoites secrete cysteine-type proteases that play a role in the adhesion of G. duodenalis to epithelial cells.

Inflammatory responses in the intestinal mucosa of gerbils and hamsters experimentally infected with the adult stage of Taenia solium.

The inflammatory response in gerbils and hamsters harbouring experimental infections with Taenia solium adult parasites as well as worm burden and duration of infections were examined. For this purpose, non-suppressed or immunosuppressed rodents were infected with eight cysticerci and necropsied at different times up to 35 days post-infection. Cells in the mucosa surrounding the implantation site of T. solium scolices (duodenum-jejunum) and in ileum were counted in stained sections. A competitive enzyme linked immunosorbent assay was used to determine histamine concentration in intestinal fluid. In non-suppressed hosts, an inflammatory reaction developed with scarce macrophages, a slight increase of plasma cells, lymphocytes and fibroblasts, a moderate increase of eosinophils and neutrophils, and high numbers of goblet and mast cells. Goblet cells began to increase at 6 days post-infection and peaked at 13 days post-infection with a four-fold increase with respect to the control group. Mast cells only increased in gerbils starting at 9 days post-infection with an eight-fold increase when cells peaked between 11 and 19 days post-infection. Histamine concentration in intestinal fluid of gerbils had a similar behaviour to mast cells. Minimal increase of mast cells was seen in hamsters. The recovery of tapeworms was inversely related to the number of both cell types, which decreased when tapeworms were eliminated. Infections lasted up to 25 days in gerbils and up to 46 days in hamsters. Worms measured only 1-2 cm in gerbils and up to 40 cm in hamsters. When gerbils were suppressed with the steroid methyl predinisolone, tapeworms could be recovered up to 35 days post-infection and tapeworms measured up to 22 cm, a minor increase of goblet and mast cells was observed and histamine concentration was similar to that in non-infected animals. Our results suggest that expulsion of T. solium in gerbils and hamsters may be related to the increase of goblet cells and mast cells, but these cells may have different roles in each rodent model of taeniosis.

Synthesis and antiprotozoal activity of novel 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives.

A series of 19 new 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives was synthesized starting from the properly substituted 1,2-phenylendiamine. These compounds have hydrogen or methyl at position 1; while hydrogen, chlorine, ethoxy or methoxycarbonyl group is at position 5 and/or 6. The novel compounds were tested against protozoa Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Experimental evaluations revealed strong activity for all tested compounds, having IC50 values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.

Benzotriazoles and Indazoles Are Scaffolds with Biological Activity against Entamoeba histolytica

Parasitic infections caused by Entamoeba histolytica are still major threats against public health, especially in developing countries. Although current therapies exist, the problems associated with parasite resistance and negative side effects make it imperative to search for new therapeutic agents. A systematic scaffold analysis reported herein of a public database containing 474 antiamoebic compounds reveals that benzimidazole is the most active scaffold reported thus far. To gain insights into the antiamoebic activity of novel compounds, the authors report herein the biological activity of 12 compounds, including benzotriazole and indazole derivatives, scaffolds not previously tested against E. histolytica. Compounds with the benzotriazole and indazole scaffolds showed low micromolar activity (IC50 = 0.304 and 0.339 µM) and are more active than metronidazole, which is the drug of choice used for the treatment of amebiosis. The novel compounds have similar properties to approved drugs. Compounds with novel scaffolds represent promising starting points of an optimization program against E. histolytica.

Trichinella spiralis: intranasal immunization with attenuated Salmonella enterica carrying a gp43 antigen-derived 30mer epitope elicits protection in BALB/c mice.

Trichinellosis is a public health problem and is considered an emergent/re-emergent disease in various countries. The etiological agent of trichinellosis is the nematode Trichinella, which infects domestic animals such as pigs and horses, as well as wild animals and humans. A veterinary vaccine could be an option to control the disease in domestic animals. Although several vaccine candidates have shown promising results, a vaccine against trichinellosis remains unavailable to date. Attenuated Salmonella strains are especially attractive live vectors because they elicit mucosal immunity, which is known to be important for the control of Trichinella spiralis infection at the intestinal level and can be administered by oral or intranasal routes. In this study, the autotransporter ShdA was used to display, on the surface of the Salmonella enterica serovar Typhimurium SL3261, the 210-239 amino acid epitope, (designated as Ag30) derived from the 43 kDa glycoprotein of T. spiralis muscle larvae. The fusion protein elicited antibodies in BALB/c mice that were able to recognize the native epitope on the surface of T. spiralis muscle larvae. Mice immunized by intranasal route with the recombinant Salmonella induced a protective immune response against the T. spiralis challenge, reducing by 61.83% the adult burden at day eight postinfection. This immune response was characterized by the induction of antigen-specific IgG1 and of IL-5 production. This study demonstrates the usefulness of Salmonella as a carrier of nematode epitopes providing a surface display system for intestinal parasite vaccine applications.

Synthesis of 3-tetrazolylmethyl-4H-chromen-4-ones via Ugi-azide and biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis

The synthesis of novel 3-tetrazolylmethyl-4H-chromen-4-ones via an Ugi-azide multicomponent reaction and their biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis are described. Reported yields are moderate to good and biological results show that these compounds could be considered as candidates to anti-parasitic drugs, especially against G. lamblia.

Hydroxyclerodanes from Salvia shannoni

Six new hydroxyclerodanes (1-6), named sepulturins A-F, and four known diterpenes were isolated from the leaves of Salvia shannoni. The structures of these compounds were established by extensive analysis of their NMR and MS spectroscopic data. The relative configurations of compounds 1 and 2 were determined by NOESY experiments and were confirmed by single-crystal X-ray diffraction studies. All of the isolated diterpenes possess tertiary OH groups. The structure of infuscatin (7), a clerodane previously isolated from S. infuscata, was revised. Cytotoxic, antiprotozoal, and anti-inflammatory activities of these compounds were evaluated.