Cytotoxicity and Leishmanicidal Activity of Isoniazid-Derived Hydrazones and 2-Pyrazineformamide Thiosemicarbazones

Raquel S Amim,Claudia Pessoa,Gisele S S Firmino,Adriane L Nery,Josane A Lessa,Jackson A L C Resende,Ana C P D Rego,Marcus V N De Souza,Silvia A G Da-Silva,José D Figueroa-Villar

doi:10.5935/0103-5053.20150330

Abstract

The isoniazid-derived hydrazones 2-pyridinecarbaldehyde- (HPCIH), 2-acetylpyridine- (HAPIH), 2-benzoylpyridine- (HBPIH), 2-pyridineformamide- (HPAmIH) and 2-pyrazineformamide- (HPzAmIH) isonicotinoyl hydrazones, as well as the pyrazinamide-derived thiosemicarbazones 2-pyrazineformamide- (HPzAm4DH), N(4)-methyl-2-pyrazineformamide- (HPzAm4M), N(4)-ethyl-2-pyrazineformamide- (HPzAm4E) and N(4)-phenyl-2-pyrazineformamide- (HPzAm4Ph) thiosemicarbazones, were assayed for their action against intracellular amastigote form of Leishmania (Viannia) braziliensis strains and the glioblastoma multiforme (SF-295), colon adenocarcinoma (HCT-116), ovarian cancer (OVCAR-8) and acute myeloid leukemia (HL-60) human tumor cell lines. All compounds exhibited leishmanicidal effects, with concentrations at which 50% of parasites were inhibited (IC50) in the 10.70-18.84 µM range. Moreover, the compounds were up to 30-fold less toxic to macrophages than to the parasites. Pyrazinamide-derived thiosemicarbazones proved to have poor activity against the tumor cell lines at 5 µg mL-1, whereas, in general the isoniazid-derived hydrazones presented good activity, being HAPIH and HBPIH the most potent compounds (IC50 = 0.42-1.5 µM).

Highlights

Cancer is one of the leading causes of death worldwide, with about 14 million new cases and 8.2 million cancer related deaths in 2012
There are a few works on antileishmanial activity of hydrazones and their thiosemicarbazone derivatives, whereas their potential as anticancer agents has been extensively investigated. 3-Aminopyridine-2carboxaldehyde thiosemicarbazone, for example, is one promising candidate for anticancer drug, which is in clinical trial for the treatment of some kinds of cancer, such as pancreatic, cervical and ovarian.[15]
Chemical shifts higher than 175 ppm observed for the signals of C8 in both compounds are typical of C=S, which suggest the thiosemicarbazones are in the thione form in solution.[16]

Summary

Introduction

Cancer is one of the leading causes of death worldwide, with about 14 million new cases and 8.2 million cancer related deaths in 2012. Mucosal forms in Brazil.[4] regarded as neglected disease, leishmaniasis occurs in 98 countries, with an annual incidence of 1 to 1.5 million people worldwide.[1,5] The treatment of leishmaniasis is restricted to a few drugs, quite costly and increasingly challenged by the development of parasite resistance.[6] In this scenario, the search for drugs that are less toxic, more effective, and less costly is critical for the treatment of leishmaniasis in endemic countries Hydrazones and their thiosemicarbazone derivatives constitute a class of chelating agents which present antileishmanial[7,8,9] and cytotoxic[10,11] activities, among others.[12,13,14] There are a few works on antileishmanial activity of hydrazones and their thiosemicarbazone derivatives, whereas their potential as anticancer agents has been extensively investigated. We have been interested in evaluating the effects of structural modification of PZA, as well as INH, by including a hydrazone or thiosemicarbazone scaffold on its antileishmanial action

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Results and Discussion

Conclusions