Exploiting Knowledge on Leishmania Drug Resistance to Support the Quest for New Drugs

Hefnawy, Aya; Berg, Maya; Dujardin, Jean‐Claude; Muylder, Géraldine De

doi:10.1016/j.pt.2016.11.003

Cited by 108 publications

(92 citation statements)

References 79 publications

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“…The results from this study were used as a basis for the development of a L. donovani genotyping methodology in Nepal and permitted an association to be made between the Leishmania genotype and the treatment applied to the patients (Rai et al, 2017). It might also be useful in identifying new drugs against leishmaniasis (Hefnawy et al, 2016). Although these studies have successfully examined intra-species genomic diversity and genes associated with visceral versus non-visceral forms of disease, an analysis of Leishmania genomes associated with different host phenotypes within a species is required to reveal possible sequence signatures or genomic structural markers associated with diverse clinical manifestations or potential host specificity.…”

Section: Introductionmentioning

confidence: 99%

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Teixeira

Monteiro

Martins

et al. 2017

International Journal for Parasitology

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The genomic sequences of 20 Leishmania infantum isolates collected in northeastern Brazil were compared with each other and with the available genomic sequences of 29 L. infantum/donovani isolates from Nepal and Turkey. The Brazilian isolates were obtained in the early 1990s or since 2009 from patients with visceral or non-ulcerating cutaneous leishmaniasis, asymptomatic humans, or dogs with visceral leishmaniasis. Two isolates were from the blood and bone marrow of the same visceral leishmaniasis patient. All 20 genomic sequences display 99.95% identity with each other and slightly less identity with a reference L. infantum genome from a Spanish isolate. Despite the high identity, analysis of individual differences among the 32 million base pair genomes showed sufficient variation to allow the isolates to be clustered based on the primary sequence. A major source of variation detected was in chromosome somy, with only four of the 36 chromosomes being predominantly disomic in all 49 isolates examined. In contrast, chromosome 31 was predominantly tetrasomic/pentasomic, consistent with its regions of synteny on two different disomic chromosomes of Trypanosoma brucei. In the Brazilian isolates, evidence for recombination was detected in 27 of the 36 chromosomes. Clustering analyses suggested two populations, in which two of the five older isolates from the 1990s clustered with a majority of recent isolates. Overall the analyses do not suggest individual sequence variants account for differences in clinical outcome or adaptation to different hosts. For the first known time, DNA of isolates from asymptomatic subjects were sequenced. Of interest, these displayed lower diversity than isolates from symptomatic subjects, an observation that deserves further investigation with additional isolates from asymptomatic subjects.

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Section: Introductionmentioning

confidence: 99%

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Teixeira

Monteiro

Martins

et al. 2017

International Journal for Parasitology

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“…parasites with low toxic side effects. Moreover, promising combination therapies are under intense investigation (4,5).…”

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confidence: 99%

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Díaz

Lucio

Moreno

et al. 2019

Antimicrob Agents Chemother

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A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC 50 ) values lower than that for the reference drug miltefosine (EC 50 , 2.84 M). In addition, the derivatives 9, 11, 42, and 47, with EC 50 between 1.1 and 1.95 M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC 50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

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“…O ensaio foi realizado com formas promastigotas de Leishmania amazonensis em fase logarítmica de crescimento. Os parasitos foram semeados em placas de cultivo celular de 96 poços contendo meio Schneider's suplementado, na quantidade de 1×10 6 Leishmania/100 μL de meio. Em seguida as substâncias HDZ-1, HDZ-2, HDZ-3, HDZ-4 e HDZ-5 foram adicionadas aos poços em triplicata e realizadas diluições seriadas, atingindo doze faixas de concentrações (0,0097 a 20 μg.mL -1 ).…”

Section: Determinação Da Concentração Inibitória Média (Ci 50 ) Das Hunclassified

“…A leitura da placa foi realizada num leitor de placas de absorbância -Biotek (modelo ELx800), no comprimento de onda de 550 nm, e os resultados foram expressos em termos de inibição do crescimento (%). O controle positivo foi realizado com 2 μg.mL -1 de anfotericina B (Anf B) diluído em meio Schneider's contendo 1×10 6 promastigotas por poço. Já o controle negativo equivaleu ao meio Schneider's contendo 1×10 6 promastigotas por poço e, neste caso, a viabilidade foi de 100% para o parasito.…”

Section: Determinação Da Concentração Inibitória Média (Ci 50 ) Das Hunclassified

“…4 Nos últimos anos tem havido relatos de casos de resistência ao tratamento com antimoniais, e uma terapêutica de substituição bem sucedida é o uso clínico do fármaco Miltefosina. 5,6 Porém, até o momento, a leishmaniose configura-se como uma doença de difícil controle devido a inexistência de vacinas para humanos, e as terapias farmacológicas disponíveis apresentam variada eficácia e segurança devido ao tempo prologado de tratamento, uma gama de reações adversas, necessidade de administração parenteral, além do possível surgimento de resistência, acarretando uma baixa adesão ao tratamento por parte dos pacientes.…”

Section: Introductionunclassified

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Síntese, Atividade Antileshmania E Citotóxica De Hidrazonas Derivadas De Aldeídos Naturais

Souza¹,

Sousa²,

Cruz³

et al. 2019

Quím. Nova

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SYNTHESIS, ANTILESHMANIA AND CYTOTOXIC ACTIVITY OF HYDRAZONES FROM NATURAL ALDEHYDES. Leishmaniasis is endemic anthropozoonosis considered to be a severe public health problem. The treatment with pentavalent antimonials presents high toxicity motivating the search for effective and less toxic drugs. Hydrazones and N-acylhydrazones are functional groups that are prominent in Medicinal Chemistry, including as antiprotozoals. In this context, five hydrazones derived from the natural aldehydes were synthesized and the molecular structures were suitably determined to employ uni and bidimensional 1 H and 13 C NMR techniques. The antileishmanial activity of all hydrazones was determined against promastigote forms of Leishmania amazonensis, and the compounds HDZ-3, HDZ-4, and HDZ-5 showed the best results, with IC 50 of 9.00, 38.10 and 26.30 μM, respectively. In the cytotoxic evaluation against RAW macrophages, HDZ-4 presented the least cytotoxic (CC 50 = 222.24 μM) and the higher selectivity. Lipinski's descriptors of the hydrazones were calculated, and the compounds HDZ-3 and HDZ-5 were more promising. These hydrazones are hybrids of natural aldehydes with drugs, the first is the result of the junction of the cinnamaldehyde with isoniazid, and the second of the vanillin with hydralazine. The results highlighted the Markush isonicotinoylhydrazone and phthalazinylhydrazone groups, molecular structures that are present in HDZ-3 and HDZ-5 and are therefore considered innovators in the development of antileishmanial drugs.

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Exploiting Knowledge on Leishmania Drug Resistance to Support the Quest for New Drugs

Cited by 108 publications

References 79 publications

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Síntese, Atividade Antileshmania E Citotóxica De Hidrazonas Derivadas De Aldeídos Naturais

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