oxadiazoles and Parasitemia

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.

Topics: 2,2'-Dipyridyl; Animals; Antimalarials; Atovaquone; Chloroquine; Drug Design; Female; Humans; Hydrazines; Mice; Mutagenicity Tests; Mutagens; Oxadiazoles; Parasitemia; Plasmodium falciparum; Pyrimethamine; Structure-Activity Relationship

The lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps of in vivo trials of novel anti-T. cruzi drug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates for in vivo assays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD.

Topics: 14-alpha Demethylase Inhibitors; Animals; Chagas Disease; Cytochrome P-450 Enzyme System; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Gene Expression; Imidazoles; Immunosuppressive Agents; Male; Mice; Nitroimidazoles; Oxadiazoles; Parasitemia; Sex Factors; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi