Alicia Hernández-Campos

Synthesis and antiparasitic activity of 1H-benzimidazole derivatives.

Compounds 1-18 have been synthesized and tested in vitro against the protozoa Giardia lamblia, Entamoeba histolytica and the helminth Trichinella spiralis. Inhibition of rat brain tubulin polymerization was also measured and compared for each compound. Results indicate that most of the compounds tested were more active as antiprotozoal agents than Metronidazole and Albendazole. None of the compounds was as active as Albendazole against T. spiralis. Although only compounds 3, 9 and 15 (2-methoxycarbonylamino derivatives) inhibited tubulin polymerization, these were not the most potent antiparasitic compounds.

Synthesis and antiparasitic activity of 2-(Trifluoromethyl)benzimidazole derivatives

2-(Trifluoromethyl)benzimidazole derivatives substituted at the 1-, 5-, and 6-positions have been synthesized and in vitro tested against the protozoa Giardia lamblia, Entamnoeha histolytica. and the helminth Trichinella spiralis. Results indicate that all the compounds tested are more active as antiprotozoal agents than Albendazole and Metronidazole. One compound (20) was as active as Albendazole against T. spiralis. These compounds were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.

Synthesis and antiparasitic activity of albendazole and mebendazole analogues.

Albendazole (Abz) and Mebendazole (Mbz) analogues have been synthesized and in vitro tested against the protozoa Giardia lamblia, Trichomonas vaginalis and the helminths Trichinella spiralis and Caenorhabditis elegans. Results indicate that compounds 4a, 4b (Abz analogues), 12b and 20 (Mbz analogues) are as active as antiprotozoal agents as Metronidazole against G. lamblia. Compound 9 was 58 times more active than Abz against T. vaginalis. Compounds 8 and 4a also shown high activity against this protozoan. Compounds 4b and 5a were as active as Abz. None of the Mbz analogues showed activity against T. vaginalis. The anthelmintic activity presented by these compounds was poor.

Structure–activity relationships of benzimidazole derivatives as antiparasitic agents: Dual activity-difference (DAD) maps

Parasitic infections still remain a major health threat in developing countries. Herein we report a systematic characterization of the structure–activity relationships (SAR) of a comprehensive set of benzimidazole derivatives tested against Trichomonas vaginalis and Giardia intestinalis. The analysis was based on pairwise comparisons of the activity similarity and molecular similarity using different molecular representations. Overall, results encourage simultaneous lead optimization efforts for benzimidazole derivatives active against both protozoan. In order to explore the activity profile of the benzimidazoles against the two parasites, we developed the dual activity-difference (DAD) map. DAD map is a complementary approach to systematically characterize the SAR of compound data sets.

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.

Adult triclabendazole-resistant Fasciola hepatica : surface and subsurface tegumental responses to in vitro treatment with the sulphoxide metabolite of the experimental fasciolicide compound alpha

Mature Fasciola hepatica of the triclabendazole-resistant Sligo isolate were incubated in vitro with 10 microg/ml of the sulphoxide metabolite of compound alpha [5-chloro-2-methylthio-6-(1-naphthyloxy)-H-benzimidazole]; the metabolite will be referred to as alpha.SO. Changes resulting from drug treatment were examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and tubulin immunocytochemistry (ICC). SEM revealed that disruption to the tegumental surface mainly took the form of swelling and blebbing. Extensive spine loss occurred on the ventral surface of the oral cone, and sloughing of the tegument was observed along the lateral margins of the fluke. Examination of sections from the anterior mid-body region at the TEM level revealed that treatment with alpha.SO led to swelling of the basal infolds and mitochondria within the tegumental syncytium; also, accumulations of secretory bodies beneath the apical plasma membrane. The tegumental cell bodies contained swollen mitochondria and cisternae of granular endoplasmic reticulum, but few Golgi complexes were observed. An increase in T2 secretory bodies was observed, whilst in the T1 tegumental cells, the T1 secretory bodies had decreased in number. Immunocytochemical (ICC) studies showed that incubation with alpha.SO, ABZ.SO and TCBZ.SO did not cause significant changes to the distribution of tubulin within the tegumental syncytium of the Sligo isolate. In contrast, alpha.SO, ABZ.SO and TCBZ.SO caused severe disruption to tubulin organization within the syncytial layer of the TCBZ-susceptible Cullompton isolate. The EM results confirm that compound alpha is a fasciolicide capable of disrupting the tegument of mature TCBZ-resistant F. hepatica; however, this was not accompanied by any change in tubulin immunoreactivity.

An evaluation of the efficacy of compound alpha and triclabendazole against two isolates of Fasciola hepatica.

Seventy indoor-reared sheep were divided into 10 groups to test the efficacy of the experimental fasciolicide, compound alpha (15mg/kg) against triclabendazole (TCBZ)-resistant and TCBZ-susceptible F. hepatica infections. Activity against the Sligo TCBZ-resistant isolate was tested at three time points post-infection (p.i.): 3 days, 4 weeks and 12 weeks (Groups 1-3, respectively). A parallel trial was carried out using TCBZ (10mg/kg) (Groups 5-7): this provided a direct comparison between the efficacies of the two drugs. Group 4 served as an untreated Sligo control. Groups 8 and 9 were setup to test the efficacy of TCBZ and compound alpha against 12-week-old and 4-week-old TCBZ-susceptible, Cullompton infections, respectively. Group 10 served as an untreated Cullompton control. Sheep were sacrificed at 16 weeks p.i. and efficacies were determined. All remaining flukes were collected and measured, before being processed for whole-mount staining to assess the condition of their reproductive structures (testis, vitellaria, ovary and uterus). A second study was carried out to test the activity of compound alpha (15mg/kg) against mature 12-week-old TCBZ-susceptible F. hepatica infections in sheep. Eighteen sheep were divided into two groups, A and B. Group A was treated and Group B served as an untreated control group. Efficacy was determined by reduction in faecal egg counts. The results showed that, whilst compound alpha was very active against adult TCBZ-susceptible flukes, producing a 100% reduction in faecal egg counts, it only caused a 62.5% reduction in fluke burden against juvenile flukes. Moreover, compound alpha was not effective against any stage of infection with TCBZ-resistant F. hepatica in sheep. Data from the trial also revealed biological differences between the two isolates. Thus, Sligo flukes were smaller in size and produced fewer eggs than the Cullompton flukes and their cysts were less infective to sheep. However, they reached the bile ducts more quickly and their eggs appeared in the faeces >2 weeks earlier.

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.

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.

Docking-based CoMFA and CoMSIA studies of non-nucleoside reverse transcriptase inhibitors of the pyridinone derivative type

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a set of pyridinone derivatives. A molecular alignment obtained by docking of compounds into the non-nucleoside reverse transcriptase inhibitor binding site of HIV-1 was used. Good correlations between the calculated binding free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. Robust and predictive 3D-QSAR models were obtained with q2 values of 0.706 and 0.723 for CoMFA and CoMSIA, respectively. The models were validated by an external test set obtaining r2 pred values of 0.720 and 0.750 for CoMFA and CoMSIA, respectively. The CoMFA, CoMSIA and docking results help to understand the type of interactions that occur between pyridinone derivatives with the non-nucleoside reverse transcriptase inhibitor binding pocket, and explain the viral resistance to pyridinone derivatives upon mutation of amino acids Tyr181 and Tyr188. The results obtained provide information for a better understanding of the drug resistant mechanisms. The 3D-QSAR models derived will be used to guide the design of pyridinone derivatives active against mutant strains of reverse transcriptase.