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 μM, LiEC50= 6.14 μM, TcEC50= 1.31 μM) 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.

Aryl thiosemicarbazones for the treatment of trypanosomatidic infections / Linciano, Pasquale; Moraes, Carolina B.; Alcantara, Laura M.; Franco, Caio H.; Pascoalino, Bruno; Freitas-Junior, Lucio H.; Macedo, Sara; Santarem, Nuno; Cordeiro-da-Silva, Anabela; Gul, Sheraz; Witt, Gesa; Kuzikov, Maria; Ellinger, Bernhard; Ferrari, Stefania; Luciani, Rosaria; Quotadamo, Antonio; Costantino, Luca; Costi, Maria Paola. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 146:(2018), pp. 423-434. [10.1016/j.ejmech.2018.01.043]

Aryl thiosemicarbazones for the treatment of trypanosomatidic infections

Linciano, Pasquale;Ferrari, Stefania;Luciani, Rosaria;Quotadamo, Antonio;Costantino, Luca;Costi, Maria Paola
2018

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= 2.31 μM, LiEC50= 6.14 μM, TcEC50= 1.31 μM) 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.
2018
31-gen-2018
146
423
434
Aryl thiosemicarbazones for the treatment of trypanosomatidic infections / Linciano, Pasquale; Moraes, Carolina B.; Alcantara, Laura M.; Franco, Caio H.; Pascoalino, Bruno; Freitas-Junior, Lucio H.; Macedo, Sara; Santarem, Nuno; Cordeiro-da-Silva, Anabela; Gul, Sheraz; Witt, Gesa; Kuzikov, Maria; Ellinger, Bernhard; Ferrari, Stefania; Luciani, Rosaria; Quotadamo, Antonio; Costantino, Luca; Costi, Maria Paola. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 146:(2018), pp. 423-434. [10.1016/j.ejmech.2018.01.043]
Linciano, Pasquale; Moraes, Carolina B.; Alcantara, Laura M.; Franco, Caio H.; Pascoalino, Bruno; Freitas-Junior, Lucio H.; Macedo, Sara; Santarem, Nuno; Cordeiro-da-Silva, Anabela; Gul, Sheraz; Witt, Gesa; Kuzikov, Maria; Ellinger, Bernhard; Ferrari, Stefania; Luciani, Rosaria; Quotadamo, Antonio; Costantino, Luca; Costi, Maria Paola
File in questo prodotto:
File Dimensione Formato  
Thiosemicarbazoni.pdf

Accesso riservato

Descrizione: Artico principale
Tipologia: Versione pubblicata dall'editore
Dimensione 1.8 MB
Formato Adobe PDF
1.8 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
POST_PRINT_linciano2018.pdf

Open access

Tipologia: Versione dell'autore revisionata e accettata per la pubblicazione
Dimensione 1.36 MB
Formato Adobe PDF
1.36 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1152907
Citazioni
  • ???jsp.display-item.citation.pmc??? 10
  • Scopus 30
  • ???jsp.display-item.citation.isi??? 27
social impact