Design, synthesis and in vitro trypanocidal and leishmanicidal activities of novel semicarbazone derivatives

Trypanosomatids are protozoan parasites that cause various diseases in human, such as leishmaniasis, Chagas disease and sleeping sickness. The highly syntenic genomes of the trypanosomatid species lead the assumption that they can encode similar proteins, indicating the possibility to design new ant...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2015-07, Vol.100, p.24-33
Main Authors: Alves, Marina A., de Queiroz, Aline C., Alexandre-Moreira, Magna Suzana, Varela, Javier, Cerecetto, Hugo, González, Mercedes, Doriguetto, Antonio C., Landre, Iara M., Barreiro, Eliezer J., Lima, Lídia M.
Format: Article
Language:English
Subjects:
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Dose-Response Relationship, Drug
Drug Design
Leishmania major - drug effects
Leishmania major - growth & development
Leishmaniasis
Models, Molecular
Molecular Conformation
Neglected diseases
Parasitic Sensitivity Tests
Peptide mimetic
Protease
Semicarbazone
Semicarbazones - chemical synthesis
Semicarbazones - chemistry
Semicarbazones - pharmacology
Structure-Activity Relationship
Trypanosoma cruzi - drug effects
Trypanosomiasis
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Summary:Trypanosomatids are protozoan parasites that cause various diseases in human, such as leishmaniasis, Chagas disease and sleeping sickness. The highly syntenic genomes of the trypanosomatid species lead the assumption that they can encode similar proteins, indicating the possibility to design new antitrypanosomatid drugs with dual trypanosomicidal and leishmanicidal activities. In this work a series of compounds (6a–h and 7a–h), containing a semicarbazone scaffold as a peptide mimetic framework, was designed and synthesized. From this series compound 7g (LASSBio-1483) highlighted, showing dual in vitro trypanosomicidal and leishmanicidal activities, with potency similar to the standard drugs nifurtimox and pentamidine. This data, taken together with its good in silico druglikeness profile and its great chemical and plasma stability, make LASSBio-1483 (7g) a new antitrypanosomatid lead-candidate. [Display omitted] •Semicarbazones with trypanosomicidal and/or leishmanicidal activities.•Semicarbazone scaffold as a peptide mimetic framework.•LASSBio-1483 (7g) a new trypanosomicidal and leishmanicidal lead-candidate.•Druglikeness properties and chemical and plasma stability.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2015.05.046