Leishmania amazonensis response to artemisinin and derivatives

Machín, Laura; Nápoles, Rachel; Gille, Lars; Monzote, Lianet

doi:10.1016/j.parint.2020.102218

Cited by 16 publications

(9 citation statements)

References 36 publications

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“…Overall, both ozonides demonstrated some antileishmanial activity, though lower than disclosed from previous in vitro studies where selected endoperoxides revealed antileishmanial potency at low micromolar (<10 µM) concentrations [ 5 , 34 ]. In the present study, the evaluation of compounds T1 and T2 was limited by their low solubility in M199 and RPMI medium.…”

Section: Resultsmentioning

confidence: 56%

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 56%

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

et al. 2022

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“…Under hypoxic conditions in mammalian cells, some EP were shown to release O 2 contributing to cell survival [ 33 ]. Against Leishmania , similar and other types of EP have been explored for their activity in vitro and in vivo, including: cyclic peroxides from marine organisms [ 34 ], ascaridole from Dysphania ambrosioides (L.) Mosyakin & Clemants [ 16 , 35 ], ergosterol endoperoxide [ 36 ], and artemisinin [ 14 , 37 ]. Although natural EP are highly interesting due to their diversity in structure, they are often difficult to synthesize de novo and, therefore, make systematic variation of structures difficult.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, also problems in the drug discovery process itself, due to the intracellular presence of Leishmania in macrophages and various in vitro models, complicate leishmaniasis drug development [ 10 , 11 ]. Organic endoperoxides (EP) of natural origin, such as artemisinin and ascaridole, have demonstrated antiprotozoal effects in vivo and in vitro against Plasmodium and Leishmania [ 12 , 13 , 14 , 15 ]. In Leishmania the prerequisite for the efficiency of EP is the abundance of iron and heme in these protozoal organisms as well as their limited protection against oxidative stress [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships

Machín

Piontek²,

Todhe³

et al. 2022

Molecules

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Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogPOW larger than 3.5 and a polar surface area smaller than 100 Å2. The most effective compounds (IC50 in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.

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“…Artemisinin and its derivatives artemether and artesunate showed in vivo anti-leishmanial activity against L. amazonensis parasites [156] and limited in vitro amastigote and promastigote activity [157]. The mechanism of action is via production of free radicals which induces parasite death in the presence of iron sources.…”

Section: Sesquiterpenesmentioning

confidence: 99%

Nanomedicine-based strategies to improve treatment of cutaneous leishmaniasis

et al. 2022

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Nanomedicine strategies were first adapted and successfully translated to clinical application for diseases, such as cancer and diabetes. These strategies would no doubt benefit unmet diseases needs as in the case of leishmaniasis. The latter causes skin sores in the cutaneous form and affects internal organs in the visceral form. Treatment of cutaneous leishmaniasis (CL) aims at accelerating wound healing, reducing scarring and cosmetic morbidity, preventing parasite transmission and relapse. Unfortunately, available treatments show only suboptimal effectiveness and none of them were designed specifically for this disease condition. Tissue regeneration using nano-based devices coupled with drug delivery are currently being used in clinic to address diabetic wounds. Thus, in this review, we analyse the current treatment options and attempt to critically analyse the use of nanomedicine-based strategies to address CL wounds in view of achieving scarless wound healing, targeting secondary bacterial infection and lowering drug toxicity.

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Leishmania amazonensis response to artemisinin and derivatives

Cited by 16 publications

References 36 publications

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships

Nanomedicine-based strategies to improve treatment of cutaneous leishmaniasis

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