Considerations about leishmaniasis and the current scenario for the development of new treatments

Leishmaniasis is a neglected disease that affects millions of people around the world, mainly socially vulnerable populations and is considered a serious public health problem. Caused by several species of the flagellated protozoa of the Leishmania genus, it is transmitted to man through female sand fly bites. The disease can present the cutaneous, mucocutaneous and visceral clinical forms, varying according to the parasite species and depending on host immune response. Depending on its evolution, the disease may pose serious risks to the afflicted individual's health. In general, treatment for Leishmaniasis is with pentavalent antimonials, in use for approximately 70 years. However, the existing treatment for Leishmaniasis presents drawbacks such as high toxicity, several side effects, cases of resistance, highlighting the need for new efficient therapeutic approaches. Given all the problems that involve the current treatment of leishmaniasis, it is of paramount importance to seek and screen new molecules that have leishmanicidal activity, meet the safety criteria, while presenting low toxicity, low cost, easy administration and that cure efficiently. This review presents some considerations on the leishmaniasis situation, its treatment and the current panorama for the development of new therapies.

Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition.

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 106 and 1.43 × 105, respectively, and DNA binding mode by intercalation. The IC50 values were obtained between 0.81 and 1.48 µM and topoisomerase inhibition results in 10 µM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.

2-(phenylthio)ethylidene derivatives as anti-Trypanosoma cruzi compounds: Structural design, synthesis and antiparasitic activity.

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The current chemotherapy is based on benznidazole, and, in some countries, Nifurtimox, which is effective in the acute phase of the disease, but its efficacy in the chronic phase remains controversial. It can also cause serious side effects that lead sufferers to abandon treatment. In the present work, is reported the synthesis and trypanocidal activity of new 2-(phenylthio)ethylidene thiosemicarbazones (4-15) and 1,3-thiazoles (16-26). The cyclization of thiosemicarbazones into 1,3-thiazoles presents an improvement in the cytotoxic profile for T. cruzi parasite, denoting selective compounds. Compound 18 was identified as the most promising of all compounds tested, showing an IC50 of 2.6 µM for the trypomastigote form and a non-cytotoxic effect on mouse spleen cells, reaching a selective index of 95.1. Among the 22 compounds tested, six compounds present a better trypanocidal activity, and five compounds have an equipotent activity compared to benznidazole. Flow cytometry and ultrastructural analysis were performed and indicate that compound 18 causes parasite cell death through apoptosis and acts via an autophagic pathway.

Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain.

The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones.