RESUMO
BACKGROUND: Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania. Current treatments are restricted to a small number of drugs that display both severe side effects and a potential for parasites to develop resistance. A new N-(3,4-methylenedioxyphenyl)-N'- (2-phenethyl) thiourea compound (thiourea 1) has shown promising in vitro activity against Leishmania amazonensis with an IC50 of 54.14 µM for promastigotes and an IC50 of 70 µM for amastigotes. OBJECTIVE: To develop a formulation of thiourea 1 as an oral treatment for leishmaniasis, it was incorporated into Nanoparticles (NPs), a proven approach to provide long-acting drug delivery systems. METHODS: Poly (D,L-Lactic-co-Glycolic Acid) (PLGA) polymeric NPs containing thiourea 1 were obtained through a nanoprecipitation methodology associated with solvent evaporation. The NPs containing thiourea 1 were characterized for Encapsulation Efficiency (EE%), reaction yield (% w/w), surface charge, particle size and morphology by Transmission Electron Microscopy (TEM). RESULTS: NPs with thiourea 1 showed an improved in vitro leishmanicidal activity with a reduction in its cytotoxicity against macrophages (CC50>100 µg/mL) while preserving its IC50 against intracellular amastigotes (1.46 ± 0.09 µg/mL). This represents a parasite Selectivity Index (SI) of 68.49, which is a marked advancement from the reference drug pentamidine (SI = 30.14). CONCLUSION: The results suggest that the incorporation into NPs potentiated the therapeutic effect of thiourea 1, most likely by improving the selective delivery of the drug to the phagocytic cells that are targeted for infection by L. amazonensis. This work reinforces the importance of nanotechnology in the acquisition of new therapeutic alternatives for oral treatments.
Assuntos
Antiprotozoários/administração & dosagem , Portadores de Fármacos/química , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Tioureia/administração & dosagem , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/toxicidade , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Humanos , Leishmaniose Cutânea/parasitologia , Macrófagos/parasitologia , Camundongos , Nanopartículas/química , Testes de Sensibilidade Parasitária , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Cultura Primária de Células , Tioureia/análogos & derivados , Tioureia/farmacocinética , Tioureia/toxicidade , Testes de Toxicidade AgudaRESUMO
In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03µM. The 8c derivative showed the highest potency against cruzain (IC50=2.4µM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
Assuntos
Tiazolidinas/farmacologia , Tiofenos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/toxicidade , Glicina/química , Camundongos , Simulação de Acoplamento Molecular , Octoxinol , Proteínas de Protozoários/antagonistas & inibidores , Tiazolidinas/síntese química , Tiazolidinas/toxicidade , Tiofenos/síntese química , Tiofenos/toxicidade , Tioureia/análogos & derivados , Tioureia/síntese química , Tioureia/farmacologia , Tioureia/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidadeRESUMO
Genotoxic activation of hydrazine (HZ), two symmetrical dialkylhydrazines, namely, 1,2dimethylhydrazine and 1,2-diethylhydrazine (SDMH and SDEH), thiourea (TU) and ethylene thiourea (ETU) has been evaluated by means of the w/w + somatic assay of Drosophila. Both low bioactivation insecticide-susceptible (IS) and high biotransformation insecticide-resistant (IR) strains were used. The combined application of insecticide-susceptible and insecticide-resistant strains should, in principle, detect somatic cell recombinagens in the Drosophila melanogaster in vivo w/w + assay. The IS strain was more susceptible to toxicity induced by the test chemicals than the IR stocks. Its performance in the biotransformation of the chemicals tested was rather poor. TU was inactive in all strains. With the active compounds, spot frequencies increased approximately linearly with dose for each spot type. SDEH gave a strong positive result in all three female genotypes exposed. HZ, ETU and SDMH were overall weakly positive in the IR strain Haag-79 (HG-R). Interestingly, ETU was clearly positive in the IR Hikone-R (HK-R) strain. A comparison of the recombinagenic potencies between the active and the weakly positive compounds, and among strains, showed pronounced genotype-dependent differences between the low and the high bioactivation strains. The ability of Drosophila to express several procarcinogens in relation to insecticide-resistance after activation catalyzed by CYP450 enzymes is discussed.