Models for cytotoxicity screening of antileishmanial drugs: what has been done so far?

Brioschi, Mariana Borges Costa; Coser, Elizabeth M.; Coelho, Adriano C.; Gadelha, Fernanda Ramos; Miguel, Danilo C.

doi:10.1016/j.ijantimicag.2022.106612

Cited by 5 publications

(6 citation statements)

References 214 publications

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“…Based on the recommendations of the WHO Special Program for Tropical Disease Research (TDR), some authors classify the compounds tested for L. donovani or L. infantum as active for an IC 50 in amastigotes in macrophages of 1-2 µg/mL, moderately active for an IC 50 between 1.0 and 6.0 µM, and inactive for an IC 50 > 6.0 µM, with a desirable SI > 10 or even > 20 [42,55,56]. This is an important step regarding antileishmanial potential, as intracellular amastigotes are the parasite forms found in mammalian hosts.…”

Section: Discussionmentioning

confidence: 99%

“…The SI is defined as the ratio of the CC 50 obtained for the host cells to the IC 50 obtained against the parasite cells and helps identify the compounds that exhibit a high degree of specificity in targeting the pathogen of interest while sparing the host cells [42,43]. To determine the SI of the selenium compounds, their cytotoxicity on murine peritoneal macrophages, NIH/3T3, and J774A.1 cells was also evaluated at concentrations ranging from 200 to 3.12 µM.…”

Section: Cytotoxicity and Simentioning

confidence: 99%

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Selenium-Containing (Hetero)Aryl Hybrids as Potential Antileishmanial Drug Candidates: In Vitro Screening against L. amazonensis

Fermiano,

das Neves,

da Silva

et al. 2024

Biomedicines

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Leishmaniasis remains a significant global health concern, with current treatments relying on outdated drugs associated with high toxicity, lengthy administration, elevated costs, and drug resistance. Consequently, the urgent need for safer and more effective therapeutic options in leishmaniasis treatment persists. Previous research has highlighted selenium compounds as promising candidates for innovative leishmaniasis therapy. In light of this, a library of 10 selenium-containing diverse compounds was designed and evaluated in this study. These compounds included selenium-substituted indole, coumarin, chromone, oxadiazole, imidazo[1,2-a]pyridine, Imidazo[2,1-b]thiazole, and oxazole, among others. These compounds were screened against Leishmania amazonensis promastigotes and intracellular amastigotes, and their cytotoxicity was assessed in peritoneal macrophages, NIH/3T3, and J774A.1 cells. Among the tested compounds, MRK-106 and MRK-108 displayed the highest potency against L. amazonensis promastigotes with reduced cytotoxicity. Notably, MRK-106 and MRK-108 exhibited IC50 values of 3.97 µM and 4.23 µM, respectively, and most of the tested compounds showed low cytotoxicity in host cells (CC50 > 200 µM). Also, compounds MRK-107 and MRK-113 showed activity against intracellular amastigotes (IC50 18.31 and 15.93 µM and SI 12.55 and 10.92, respectively). In conclusion, the identified selenium-containing compounds hold potential structures as antileishmanial drug candidates to be further explored in subsequent studies. These findings represent a significant step toward the development of safer and more effective therapies for leishmaniasis, addressing the pressing need for novel and improved treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Cytotoxicity and Simentioning

confidence: 99%

Selenium-Containing (Hetero)Aryl Hybrids as Potential Antileishmanial Drug Candidates: In Vitro Screening against L. amazonensis

Fermiano,

das Neves,

da Silva

et al. 2024

Biomedicines

View full text Add to dashboard Cite

show abstract

“…Based on the recommendations of the World Health Organization (WHO) Special Programme for Tropical Disease Research (TDR), some authors classify the compounds tested for L. donovani or L. infantum as active for an IC50 in amastigotes in macrophages of 1-2 µg/ml, moderately active for IC50 between 1.0 and 6.0 µM, and inactive for IC50 >6.0 µM, with a desirable SI>10 or even >20 [42,55,56]. This is an important step regarding antileishmanial potential, as intracellular amastigotes are the parasite forms found in mammalian host.…”

Section: Discussionmentioning

confidence: 99%

“…The selectivity index (SI) is defined as the ratio of the CC50 obtained for host cells to the IC50 obtained against the parasite cells and helps identify the compounds that exhibit a high degree of specificity in targeting the pathogen of interest while sparing host cells [42,43]. To determine the selectivity index of the selenium compounds, their cytotoxicity on murine peritoneal macrophages, NIH/3T3 murine fibroblast cell line and J774A.1 murine macrophages cell line was also evaluated, at concentrations ranging from 200 to 3.12 µM.…”

Section: Cytotoxicity and Selectivity Indexmentioning

confidence: 99%

Selenium-Containing (Hetero)Aryl Hybrids as Potential Antileishmanial Drug Candidates: In vitro Screening Against L. amazonensis

Fermiano,

Das Neves,

Da Silva

et al. 2023

Preprint

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Leishmaniasis remains a significant global health concern, with current treatments relying on outdated drugs associated with high toxicity, lengthy administration, elevated costs, and drug resistance. Consequently, the urgent need for safer and more effective therapeutic options in leishmaniasis treatment persists. Previous research has highlighted selenium compounds as promising candidates for innovative leishmaniasis therapy. In light of this, a library of 10 selenium-containing diverse compounds was designed and evaluated in this study. The compounds were subjected to screening against L. amazonensis promastigotes, and their cytotoxicity was assessed in NIH/3T3 cells. Among the tested compounds, MRK-106 and MRK-108 displayed the highest potency against L. amazonensis promastigotes while demonstrating reduced cytotoxicity. Notably, MRK-106 and MRK-108 exhibited IC50 values of 3.97 µM, 4.23 µM, respectively, and most of the tested compounds showed low cytotoxicity in NIH/3T3 cells (CC50 &gt; 200 µM). Although these results are promising, additional investigations focusing on intracellular amastigotes are required to determine the antileishmanial activity of the compounds. In conclusion, the identified selenium-containing compounds hold considerable potential as antileishmanial drug candidates and warrant further exploration in subsequent studies. These findings represent a significant step towards the development of safer and more effective therapies for leishmaniasis, addressing the pressing need for novel and improved treatments.

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“…For (A), one has to consider that the lack of uniformity regarding the choice of cell types for cytotoxicity assays may lead to incomparable and inconclusive data. In vitro assays relying solely on non-phagocytic cell models may not represent a realistic result, as the effect of an anti-leishmanial agent should ideally be presented based on its cytotoxicity profile against reticuloendothelial system cells [ 65 ]. In the Leishmania studies, we used the macrophage cell line J774A.1 [ 66 , 67 , 68 ], as a cytopathogenicity control test organism (see Section 2 Materials and Methods).…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Peptides (AMP) in the Cell-Free Culture Media of Xenorhabdus budapestensis and X. szentirmaii Exert Anti-Protist Activity against Eukaryotic Vertebrate Pathogens including Histomonas meleagridis and Leishmania donovani Species

Fodor,

Hess,

Ganas

et al. 2023

Antibiotics

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Anti-microbial peptides provide a powerful toolkit for combating multidrug resistance. Combating eukaryotic pathogens is complicated because the intracellular drug targets in the eukaryotic pathogen are frequently homologs of cellular structures of vital importance in the host organism. The entomopathogenic bacteria (EPB), symbionts of entomopathogenic–nematode species, release a series of non-ribosomal templated anti-microbial peptides. Some may be potential drug candidates. The ability of an entomopathogenic–nematode/entomopathogenic bacterium symbiotic complex to survive in a given polyxenic milieu is a coevolutionary product. This explains that those gene complexes that are responsible for the biosynthesis of different non-ribosomal templated anti-microbial protective peptides (including those that are potently capable of inactivating the protist mammalian pathogen Leishmania donovanii and the gallinaceous bird pathogen Histomonas meleagridis) are co-regulated. Our approach is based on comparative anti-microbial bioassays of the culture media of the wild-type and regulatory mutant strains. We concluded that Xenorhabdus budapestensis and X. szentirmaii are excellent sources of non-ribosomal templated anti-microbial peptides that are efficient antagonists of the mentioned pathogens. Data on selective cytotoxicity of different cell-free culture media encourage us to forecast that the recently discovered “easy-PACId” research strategy is suitable for constructing entomopathogenic-bacterium (EPB) strains producing and releasing single, harmless, non-ribosomal templated anti-microbial peptides with considerable drug, (probiotic)-candidate potential.

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Models for cytotoxicity screening of antileishmanial drugs: what has been done so far?

Cited by 5 publications

References 214 publications

Selenium-Containing (Hetero)Aryl Hybrids as Potential Antileishmanial Drug Candidates: In Vitro Screening against L. amazonensis

Selenium-Containing (Hetero)Aryl Hybrids as Potential Antileishmanial Drug Candidates: In Vitro Screening against L. amazonensis

Selenium-Containing (Hetero)Aryl Hybrids as Potential Antileishmanial Drug Candidates: In vitro Screening Against L. amazonensis

Antimicrobial Peptides (AMP) in the Cell-Free Culture Media of Xenorhabdus budapestensis and X. szentirmaii Exert Anti-Protist Activity against Eukaryotic Vertebrate Pathogens including Histomonas meleagridis and Leishmania donovani Species

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