Review of Theoretical Models to Study Natural Products with Antiprotozoal Activity.

In nature, pathogenic parasite species with different susceptibility patterns of antiparasitic drugs abound. In this sense, natural products derived from plants are a potency for drugs with potential antiparasitic activity. Unfortunately, there are many metabolites and studying all of them would be costly in terms of money and resources. To this end, theoretical studies such as QSAR models could be useful. These, for the most part, predict the biological activity of the drugs against a single species of parasite. Consequently, foretell the probability with which a drug is active against many different species with a single QSAR model is an important achievement. This review consists of three parts: the first part is a review of metabolites found in nature that have antiparasitic activity, in particular the antiprotozoal (Leishmania and Trypanosoma); the second part includes a review of theoretical studies looking for a model that predicts the antiprotozoal activity of natural products; the third and final part concerns the study of theoretical models focused on the interaction between drug and receptor, analyzing new metabolites with antiprotozoal activity.

Synthesis, Screening and in silico Simulations of Anti-Parasitic Propamidine/Benzimidazole Derivatives.

BACKGROUND: We designed hybrid molecules between propamidine and benzimidazole in order to retain the antiprotozoal action, but decreasing the toxic effect of the molecule. OBJECTIVE: Design and prepare 12 hybrids for testing their antiparasitic effect over three protozoa: Giardia intestinalis, Trichomonas vaginalis and Leishmania mexicana, as well as conduct several in silico simulations such as toxicological profile, molecular docking and molecular dynamics in order to understand their potential mode of action. METHODS: Hybrids 1-3, 6-9 and 12 were obtained using a chemical pathway previously reported. Compounds 4, 5, 10 and 11 were prepared using a one-pot reduction-cyclization reaction. The in vitro antiparasitic and cytotoxic activities of these compounds were conducted. It was calculated several properties such as toxicity, PK behavior, as well as docking studies and molecular dynamics of the most active compound performed in a DNA sequence dodecamer in comparison with propamidine. RESULTS: Compound 2 was 183, 127 and 202 times more active against G. intestinalis than metronidazole, pentamidine and propamidine. It was eleven times more active than pentamidine against L. mexicana. This compound showed low in vitro mammalian cytotoxicity. Molecular simulations showed a stable complex 2-DNA that occurred in the minor groove, analogous to propamidine-DNA complex. CONCLUSION: Compound 2, exhibited the higher bioactivity, especially towards G. intestinalis and L. mexicana. This study demonstrated that the replacement of benzimidazole scaffold instead of toxic amidine group in propamidine, results in an enhancement of antiprotozoal bioactivity. The preliminary molecular dynamics simulation suggests that the ligand-DNA complex is stable.