Chiral brønsted Acid-catalyzed stereoselective Mannich-type reaction of azlactones with aldimines.

A highly diastereo- and enantioselective Mannich-type reaction of azlactones with aldimines catalyzed by a chiral phosphoric acid is described. Only 3 mol % catalyst was required to prepare the Mannich adducts in good yields with high stereochemical control (up to >19:1 dr, >99:1 er). Moreover, the final product contains two consecutive stereogenic centers, one of which is quaternary.

Zinc(II)-Sterol Hydrazone Complex as a Potent Anti-Leishmania Agent: Synthesis, Characterization, and Insight into Its Mechanism of Antiparasitic Action.

Searching for new alternatives for treating leishmaniasis, we present the synthesis, characterization, and biological evaluation against Leishmania amazonensis of the new ZnCl2(H3)2 complex. H3 is 22-hydrazone-imidazoline-2-yl-chol-5-ene-3ß-ol, a well-known bioactive molecule functioning as a sterol Δ24-sterol methyl transferase (24-SMT) inhibitor. The ZnCl2(H3)2 complex was characterized by infrared, UV-vis, molar conductance measurements, elemental analysis, mass spectrometry, and NMR experiments. The biological results showed that the free ligand H3 and ZnCl2(H3)2 significantly inhibited the growth of promastigotes and intracellular amastigotes. The IC50 values found for H3 and ZnCl2(H3)2 were 5.2 µM and 2.5 µM for promastigotes, and 543 nM and 32 nM for intracellular amastigotes, respectively. Thus, the ZnCl2(H3)2 complex proved to be seventeen times more potent than the free ligand H3 against the intracellular amastigote, the clinically relevant stage. Furthermore, cytotoxicity assays and determination of selectivity index (SI) revealed that ZnCl2(H3)2 (CC50 = 5 µΜ, SI = 156) is more selective than H3 (CC50 = 10 µΜ, SI = 20). Furthermore, as H3 is a specific inhibitor of the 24-SMT, free sterol analysis was performed. The results showed that H3 was not only able to induce depletion of endogenous parasite sterols (episterol and 5-dehydroepisterol) and their replacement by 24-desalkyl sterols (cholesta-5,7,24-trien-3ß-ol and cholesta-7,24-dien-3ß-ol) but also its zinc derivative resulting in a loss of cell viability. Using electron microscopy, studies on the fine ultrastructure of the parasites showed significant differences between the control cells and parasites treated with H3 and ZnCl2(H3)2. The inhibitors induced membrane wrinkle, mitochondrial injury, and abnormal chromatin condensation changes that are more intense in the cells treated with ZnCl2(H3)2.

Metallodrugs for the Treatment of Trypanosomatid Diseases: Recent Advances and New Insights.

Trypanosomatid parasites are responsible for many Neglected Tropical Diseases (NTDs). NTDs are a group of illnesses that prevail in low-income populations, such as in tropical and subtropical areas of Africa, Asia, and the Americas. The three major human diseases caused by trypanosomatids are African trypanosomiasis, Chagas disease and leishmaniasis. There are known drugs for the treatment of these diseases that are used extensively and are affordable; however, the use of these medicines is limited by several drawbacks such as the development of chemo-resistance, side effects such as cardiotoxicity, low selectivity, and others. Therefore, there is a need to develop new chemotherapeutic against these tropical parasitic diseases. Metal-based drugs against NTDs have been discussed over the years as alternative ways to overcome the difficulties presented by approved antiparasitic agents. The study of late transition metal-based drugs as chemotherapeutics is an exciting research field in chemistry, biology, and medicine due to the ability to develop multitarget antiparasitic agents. The evaluation of the late transition metal complexes for the treatment of trypanosomatid diseases is provided here, as well as some insights about their mechanism of action.