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1.
Molecules ; 25(11)2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32486239

RESUMO

High genetic and phenotypic variability between Leishmania species and strains within species make the development of broad-spectrum antileishmanial drugs challenging. Thus, screening panels consisting of several diverse Leishmania species can be useful in enabling compound prioritization based on their spectrum of activity. In this study, a robust and reproducible high content assay was developed, and 1280 small molecules were simultaneously screened against clinically relevant cutaneous and visceral species: L. amazonensis, L. braziliensis, and L. donovani. The assay is based on THP-1 macrophages infected with stationary phase promastigotes and posterior evaluation of both compound antileishmanial activity and host cell toxicity. The profile of compound activity was species-specific, and out of 51 active compounds, only 14 presented broad-spectrum activity against the three species, with activities ranging from 52% to 100%. Notably, the compounds CB1954, Clomipramine, Maprotiline, Protriptyline, and ML-9 presented pan-leishmanial activity, with efficacy greater than 70%. The results highlight the reduced number of compound classes with pan-leishmanial activity that might be available from diversity libraries, emphasizing the need to screen active compounds against a panel of species and strains. The assay reported here can be adapted to virtually any Leishmania species without the need for genetic modification of parasites, providing the basis for the discovery of broad spectrum anti-leishmanial agents.


Assuntos
Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Leishmania/efeitos dos fármacos , Leishmania/patogenicidade , Leishmaniose Visceral/tratamento farmacológico , Maprotilina/química , Camundongos , Protriptilina/química , Especificidade da Espécie , Células THP-1
2.
Molecules, v. 25, n. 11, 2551, mai. 2020
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-3058

RESUMO

High genetic and phenotypic variability between Leishmania species and strains within species make the development of broad-spectrum antileishmanial drugs challenging. Thus, screening panels consisting of several diverse Leishmania species can be useful in enabling compound prioritization based on their spectrum of activity. In this study, a robust and reproducible high content assay was developed, and 1280 small molecules were simultaneously screened against clinically relevant cutaneous and visceral species: L. amazonensis, L. braziliensis, and L. donovani. The assay is based on THP-1 macrophages infected with stationary phase promastigotes and posterior evaluation of both compound antileishmanial activity and host cell toxicity. The profile of compound activity was species-specific, and out of 51 active compounds, only 14 presented broad-spectrum activity against the three species, with activities ranging from 52% to 100%. Notably, the compounds CB1954, Clomipramine, Maprotiline, Protriptyline, and ML-9 presented pan-leishmanial activity, with efficacy greater than 70%. The results highlight the reduced number of compound classes with pan-leishmanial activity that might be available from diversity libraries, emphasizing the need to screen active compounds against a panel of species and strains. The assay reported here can be adapted to virtually any Leishmania species without the need for genetic modification of parasites, providing the basis for the discovery of broad spectrum anti-leishmanial agents.

3.
Int J Parasitol Drugs Drug Resist ; 8(3): 430-439, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30293058

RESUMO

Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use. Drug-resistant parasite strains are also a matter for increasing concern, especially in areas with very limited resources. The current scenario calls for novel and/or improvement of existing therapeutics as key research priorities in the field. Although several studies have shown advances in drug discovery towards leishmaniasis in recent years, key knowledge gaps in drug discovery pipelines still need to be addressed. In this review we discuss not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.


Assuntos
Descoberta de Drogas/métodos , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Doença de Chagas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/estatística & dados numéricos , Descoberta de Drogas/legislação & jurisprudência , Descoberta de Drogas/estatística & dados numéricos , Descoberta de Drogas/tendências , Humanos , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Parcerias Público-Privadas , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Trypanosomatina/efeitos dos fármacos
4.
Eur J Med Chem, v. 146, p. 423-434, fev. 2018
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-2419

RESUMO

Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50=231 mu M, LiEC50 = 6.14 mu M, TcEC50 = 1.31 mu M) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6 fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.

5.
Bioorg Med Chem Lett ; 27(11): 2459-2464, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28434763

RESUMO

Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2-10.98µM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50µM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.


Assuntos
Antiprotozoários/farmacologia , Chalconas/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Leishmania infantum/efeitos dos fármacos , Nitrofuranos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Anfotericina B/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Chalconas/síntese química , Chalconas/química , Chlorocebus aethiops , Simulação por Computador , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Bases de Dados Factuais , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Nitrofuranos/síntese química , Nitrofuranos/química , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Células Vero
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