Aryl thiosemicarbazones for the treatment of trypanosomatidic infections

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Linciano, P (Author) Other; Moraes, CB (Author) Other; Alcantara, LM (Author) Other; Franco, CH (Author) Other; Pascoalino, B (Author) Other; Freitas Junior, LH (Author) Other; Macedo, S (Author) Other; Santarem, N (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Gul, S (Author) Other; Witt, G (Author) Other; Kuzikov, M (Author) Other; Ellinger, B (Author) Other; Ferrari, S (Author) Other; Luciani, R (Author) Other; Quotadamo, A (Author) Other; Costantino, L (Author) Other; Costi, MP (Author) Other

Journal

Title: European Journal of Medicinal Chemistry

Vol. 146

Pages: 423-434

ISSN: 0223-5234

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 5 Citations

Scopus - 17 Citations

Other information

Authenticus ID: P-00N-M0V

DOI: 10.1016/j.ejmech.2018.01.043

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12