Aryl thiosemicarbazones for the treatment of trypanosomatidic infections

Autor: Maria Kuzikov, Gesa Witt, Bruno dos Santos Pascoalino, Caio Haddad Franco, Luca Costantino, Rosaria Luciani, Laura M. Alcantara, Nuno Santarém, Sara Macedo, Antonio Quotadamo, Lucio H. Freitas-Junior, Bernhard Ellinger, Carolina B. Moraes, Stefania Ferrari, Maria Paola Costi, Sheraz Gul, Anabela Cordeiro-da-Silva, Pasquale Linciano
Přispěvatelé: Publica
Rok vydání: 2018
Předmět:
Thiosemicarbazones
0301 basic medicine
Trypanosoma
Stereochemistry
hERG
Antiprotozoal Agents
Trypanosoma brucei
01 natural sciences
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Parasitic Sensitivity Tests
Thiadiazoles
Early-toxicity
Leishmania infantum
pan-anti-trypanosomatidic activity
Thiosemicarbazone
Trypanosoma cruzi
Pharmacology
Drug Discovery3003 Pharmaceutical Science
Organic Chemistry
parasitic diseases
Drug Discovery
medicine
Humans
Chagas Disease
Amastigote
Semicarbazone
Dose-Response Relationship
Drug
Molecular Structure
biology
Macrophages
General Medicine
biology.organism_classification
medicine.disease
0104 chemical sciences
3. Good health
010404 medicinal & biomolecular chemistry
Mitochondrial toxicity
030104 developmental biology
chemistry
biology.protein
Zdroj: European Journal of Medicinal Chemistry. 146:423-434
ISSN: 0223-5234
Popis: 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 = 2.31 mM, LiEC50 = 6.14 mM, TcEC50 = 1.31 mM) 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.
Databáze: OpenAIRE
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