Aryl thiosemicarbazones for the treatment of trypanosomatidic infections


Publication type
Article
Language
English
Appears in Collections:
Metrics
Abstract
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.
Reference
Linciano P, Moraes CB, Alcantara LM., Franco CH, Pascoalino B, Freitas-Junior LHG, et al. Aryl thiosemicarbazones for the treatment of trypanosomatidic infections. Eur J Med Chem. 2018 Feb;146:423-34. doi:10.1016/j.ejmech.2018.01.043.
Link to cite this reference
https://repositorio.butantan.gov.br/handle/butantan/2419
Issue Date
2018


Files in This Item:

Existing users please Login
10.1016j.ejmech.2018.01.043.pdf
Size: 1.87 MB
Format: Adobe PDF
Embargoed until January 1, 2999    Request a copy
Show full item record

The access to the publications deposited in this repository respects the licenses from journals and publishers.