Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) is a critical flavoenzyme in Mycobacterium tuberculosis, catalyzing a vital step in the production of lipoarabinomannan and arabinogalactan, both of which are essential for cell wall biosynthesis. Due to its periplasmic localization, DprE1 is a susceptible target, and several compounds with diverse scaffolds have been discovered that inhibit this enzyme, covalently or noncovalently. We evaluated a total of ∼1519 DprE1 inhibitors disclosed in the literature from 2009 to April 2022 by performing an in-depth analysis of physicochemical descriptors and absorption, distribution, metabolism, excretion, and toxicity (ADMET), to gain new insights into these properties in DprE1 inhibitors. Several molecular properties that should facilitate the design and optimization of future DprE1 inhibitors are described, allowing for the development of improved analogues targeting M. tuberculosis.

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC₅₀ values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC₅₀ value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.

Leishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on Leishmania parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against L. infantum and L. donovani and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 Leishmania species, with IC₅₀ values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on L. infantum amastigotes (IC₅₀ 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes.

Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1 •HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead.

The accumulation of marine biotoxins in shellfish and their consumption causes serious food safety problems, threatening human health and compromising the availability of protein-based food. It is thus urgent to develop methodologies for the detoxification of live bivalves, avoiding their economic and nutritional devaluation. In this context, we tested an adsorption mechanism of paralytic shellfish toxins (PST) based on a cation-exchange resin. The first studies using cultures of Gymnodinium catenatum (natural producers of PST) showed a decrease of about 80% in overall toxicity after 48 h. Interestingly, we found that the toxins are adsorbed differently, with toxins’ structural features playing a part in the adsorption capacity via steric hindrance, electronic effects, or the extent of positive charge density (e.g., dcSTX). The positive effect of the resin in accelerating PST clearance from live mussels (Mytilus edulis) is not evident when compared to resin-free clearance; nevertheless, relevant information could be gathered that will facilitate further in vivo studies. Several factors appear to be at play, namely the competition of natural substances (e.g., salts, organic matter) for the same binding sites, the blocking of pores due to interactions between molecules, and/or difficulties in resin absorption by mussels. Additionally, the present work revealed the ability of mussels to neutralize pH and proposes bioconversion reactions among the PST molecules.