Toxoplasmosis is an infectious disease with paramount impact worldwide, affecting many vulnerable populations and representing a significant matter of concern. Current therapies used against toxoplasmosis are based essentially on old chemotypes, which fail in providing a definitive cure for the disease, placing the most sensitive populations at risk for irreversible damage in vital organs, culminating in death in the most serious cases. Antimalarial drugs have been shown to possess key features for drug repurposing, finding application in the treatment of other parasite-borne illnesses, including toxoplasmosis. Antimalarials provide the most effective therapeutic solutions against toxoplasmosis and make up for the majority of currently available antitoxoplasmic drugs. Additionally, other antiplasmodial drugs have been scrutinized and many promising candidates have emanated in recent developments. Available data demonstrate that it is worthwhile to explore the activity of classical and most recent antimalarial chemotypes, such as quinolines, endoperoxides, pyrazolo[1,5-a]pyrimidines, and nature-derived peptide-based parasiticidal agents, in the context of toxoplasmosis chemotherapy, in the quest for encountering more effective and safer tools for toxoplasmosis control or eradication.

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.

Neglected Tropical Diseases (NTDs) encompass a range of disorders, including infectious diseases caused by viruses, bacteria, parasites, fungi, and toxins, mainly affecting underprivileged individuals in developing countries. Among the NTDs, those caused by parasites belonging to the Trypanosomatidae family are particularly impacting and require attention, since the lack of financial incentives has led to constraints on the development of novel drugs to tackle them effectively. To circumvent the minor advances in drug discovery in this area, academic research emerges as a crucial player, namely through the identification and validation of new drug targets, thereby contributing to the development of more efficient, safe, and less expensive therapies against Trypanosomatidae infections. Noteworthy, this is a matter of utmost urgency since these diseases are endemic in countries with low socioeconomic standards. This review provides a comprehensive understanding of the current paradigm of NTDs caused by parasites belonging to the Trypanosomatidae family, addressing the ongoing limitations and challenges associated to the current chemotherapy solutions for these diseases and discussing the opportunities unravelled by recent research that led to the identification of new biomolecular targets that are common to Trypanosomatidae parasites. Among these, the unique properties of Trypanothione Synthetase (TryS) and Trypanothione Reductase (TryR), two key protozoan enzymes that are essential for the survival of Trypanosoma and Leishmania parasites, will be emphasised. In addition to a critical analysis of the latest advances in the discovery of novel molecules capable of inhibiting TryS and TryR, the possibility of dual targeting through a combination of TryS and TryR inhibitors will be addressed

Endoperoxide-containing molecules based on the antimalarial drug artemisinin have demonstrated various biological properties, including modulation of calcium homeostasis. This study evaluated the toxicity and osteogenic activity of five newly developed tetraoxanes (YB1, YB9, YB11, YB17 and T2), alongside three of their non-peroxidic analogues (IC22, IC26 and IC33), in zebrafish (Danio rerio) larvae. For each compound, LC₅₀ values were first determined. Behavioural responses and morphological alterations were studied as indicators of toxicological impact. The osteogenic activity was assessed through the operculum assay, followed by the analysis of gene expression markers related to calcium homeostasis (atp2a1), oxidative stress (sod1, cat), and osteogenesis (sp7, oc2). All the compounds evaluated induced an inhibition of osteogenic activity. T2, YB11, IC33 and IC26 affected the locomotor function by decreasing swimming activity. IC26 and IC33 induced morphological toxicity, characterized by a curved trunk and alterations in larval body curvature. From all the compounds studied, YB1, YB9, YB17 and IC22 showed selective anti-osteogenic activity, without displaying significant behavioural or morphological toxicity. In conclusion, the presence of a peroxide bond in the molecular structure of the compounds increases the anti-osteogenic activity at lower concentrations. All evaluated compounds exhibited anti-osteogenic activity and can be regarded as anti-osteogenic agents. However, YB17 did not induce transcription alterations in the genes analyzed and may thus represent the most promising compound in conditions where a controlled inhibition of bone formation is desirable.

Conception, synthèse et évaluation d'hybrides à base d'endoperoxydes et d'inhibiteurs de la trypanothione réductase comme nouveaux candidats antiparasitaires: Les leishmanioses constituent un ensemble de pathologies causées par des parasites du genre Leishmania et figurent parmi les 13 maladies tropicales négligées reconnues par l'Organisation mondiale de la santé (OMS). Elles se présentent sous trois formes principales: viscérale, cutanée et mucocutanée. Malgré les progrès réalisés, le traitement repose sur un arsenal thérapeutique limité, associé à une toxicité importante, à des coûts élevés, à des protocoles longs et à l'émergence de résistances.Dans cette perspective, la présente thèse s'articule autour de trois approches complémentaires visant à améliorer la chimiothérapie antileishmanienne. Après une introduction générale consacrée au parasite (Chapitre 1), le Chapitre 2 explore la première stratégie: la synthèse de novo de composés actifs. Parmi les cibles enzymatiques étudiées, la trypanothione réductase (TryR) s'est révélée essentielle au maintien de l'équilibre rédox du parasite, en réduisant la trypanothione disulfure (TS₂) en trypanothione réduite (T(SH)₂). Cette enzyme, commune à tous les Trypanosomatidae mais absente chez les mammifères, représente une cible privilégiée. Sur la base d'études antérieures montrant que les pyrimidine-thioéthers peuvent inhiber TryR, une nouvelle série de dérivés pyrimidiques a été préparée par la réaction de Buchwald-Hartwig.Les essais in vitro réalisés sur les formes axéniques et amastigotes intramacrophagiques de L. donovani et L. major ont identifié les composés 6, 13 et 15 comme les plus prometteurs, avec des IC50 inférieures à celles de la miltéfosine (2,9 µM). Les analyses in silico ont confirmé leur interaction avec plusieurs résidus du site de liaison au NADPH (Arg222, Arg228, Tyr221), suggérant une interférence avec le cofacteur et une inhibition potentielle de l'enzyme. Les tests de cytotoxicité ont permis d'écarter le composé 13, tandis que les composés 6 et 15 ont été retenus pour des évaluations complémentaires.Le Chapitre 3 s'intéresse au repositionnement de médicaments, une approche plus rapide et économiquement avantageuse. Les endoperoxydes, déjà utilisés comme antipaludiques de première ligne, ont été réévalués pour leur potentiel contre Leishmania. Bien que leur mécanisme d'action chez Plasmodium, impliquant la formation de radicaux alkylants après rupture du pont peroxyde, soit bien connu, celui exercé sur Leishmania reste largement méconnu. Pour mieux comprendre ce rôle, vingt-sept composés ont été synthétisés, comprenant treize peroxydes et quatorze analogues désoxygénés. Les résultats biologiques obtenus sur L. major et L. donovani (formes axéniques et intracellulaires) n'ont montré aucune différence significative d'activité, indiquant que la liaison peroxyde n'est peut-être pas le principal déterminant de l'effet antileishmanien et que d'autres mécanismes, distincts de ceux du paludisme, pourraient intervenir.Enfin, le Chapitre 4 présente l'approche de l'hybridation moléculaire, consistant à associer plusieurs pharmacophores au sein d'une même entité chimique afin d'accroître la puissance, de limiter les effets secondaires et de réduire le risque de résistance. Compte tenu du potentiel des endoperoxydes, ceux-ci ont été intégrés à des structures hybrides en association avec des pyrazoles, des pyrimidine-thioéthers et la miltéfosine. Douze nouveaux hybrides, ainsi que plusieurs sels correspondants, ont été préparés et testés sur différentes espèces de Leishmania (L. infantum, L. tropica, L. donovani et L. major). Les hybrides endoperoxyde-pyrimidine-thioéther, y compris le témoin tétraoxane, ont affiché des IC50 inférieures ou comparables à celles de la miltéfosine (< 3,1 µM) contre les formes amastigotes intracellulaires de L. donovani et L. major. Le dérivé tétraoxane-miltéfosine (composé 56) s'est également distingué par une forte activité (IC50, 4,0 µM), justifiant sa sélection pour de futures études in vivo aux côtés des hybrides endoperoxyde-pyrimidine-thioéther.

Skin functionalities are instrumental in four main domains: protection, regulation, sensation, and support. However, excessive exposure to ultraviolet (UV) radiation can compromise skin integrity and, in turn, affect its functions, by generating reactive oxygen species (ROS). Aiming to protect skin from UV radiation, sunscreens incorporate UV filters and antioxidants that absorb/reflect UV rays and neutralise free radicals, respectively. Nevertheless, undesired side and ecological effects of conventional UV filters have spurred the search for safer alternatives. Among synthetic antioxidants, thioethers have attracted attention for their redox power and potential medicinal properties. In this context, a library of aminopyrimidine–arylthioether conjugates was synthesised and evaluated for their antioxidant, enzyme-inhibitory and antibacterial activities, as well as for their cytotoxicity in HaCaT cells and potential photoprotective properties. Among the aminopyrimidine-thioethers studied, compound C5 stood out for its antioxidant potential, exhibiting a value of 566.39 mM FeSO₄ equivalents per mM of the compound, while compound C2 showed the highest anti-enzymatic potential, inhibiting elastase (45.58%) and tyrosinase activities (34.66%). Regarding photoprotective activity, compound C13 reduced by 33.74% the ROS production induced by UV radiation exposure, at 100 μM, a non-cytotoxic concentration. Finally, compound C7 inhibited the growth of Staphylococcus epidermidis, Staphylococcus hominis and Cutibacterium acnes, at 30 μM. These preliminary results demonstrate that aminopyrimidine–arylthioethers constitute a new class of compounds warranting further investigation for skin protection. Compound C5 showed antioxidant activity in the FRAP assay, comparable to that of the positive control, BHT.