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1.
Chem Biol Interact ; 283: 20-29, 2018 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-29366735

RESUMEN

Schistosomiasis is considered a serious public health problem in 78 countries and territories located in Africa, Asia and America and it is estimated in more than 249 million people infected by any of the species of Schistosoma. The exclusive use of praziquantel (PZQ), effective drug against all species of Schistosoma, has been the basis of the development of a possible resistance against the strains of this parasite. In addition, PZQ is not effective against young forms of worms. Thus, there is a need for the development of new drugs with schistosomicidal activity. The objective of this work was to synthesize and to evaluate the therapeutic potential of new benzodioxole derivatives (3-14) candidates for schistosomicidal drugs. All compounds synthesized showed in vitro schistosomicidal activity. The derivative 12 was considered the best compound, since it took 100% of worms to mortality in the first 72 h of exposure at the concentration of 100 µM and 83.3% at the concentration of 50 µM. Furthermore, male and female adult worms, incubated for 24 h with the compound 12 showed tegument damages characterized by extensive desquamation and edema, tuber destruction, bubble formation and exposure of the muscle layer. This compound has a restricted structure, where the thiazolidinone is attached to the 4-position of the 1,3-benzodioxol ring. The structural conformation of derivative 12 was probably responsible for the promising schistosomicidal activity, where the presence of an electron/conformational restriction of the thiazolidine ring, as well as the action of bromine as a bulk substitute, favored an increase in biological activity. In addition, tegumentary changes caused by derivative 12 may also have been responsible for the death of adult worms of Schistosoma mansoni. Therefore, we verified that the results obtained in this study make benzodioxole derivatives possible candidates for prototypes of new schistosomicidal drugs.


Asunto(s)
Dioxoles/química , Dioxoles/farmacología , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/síntesis química , Esquistosomicidas/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Dioxoles/uso terapéutico , Células HeLa , Humanos , Microscopía Electrónica de Rastreo , Praziquantel/farmacología , Praziquantel/uso terapéutico , Schistosoma mansoni/ultraestructura , Esquistosomiasis/tratamiento farmacológico , Esquistosomiasis/patología , Esquistosomicidas/uso terapéutico
2.
Biomed Pharmacother ; 83: 502-507, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27434866

RESUMEN

Praziquantel has been the drug most widely used therapy against different forms of schistosomiasis around the world. However, this treatment has shown ineffective in humans and in experimental models of Schistosoma mansoni. New therapeutic alternatives have been tested, including the imidazolidine derivative LPSF/PT-09, which has shown high therapeutic potential in vitro. In this work, we tested the schistosomal activity of this derivative in doses of 250mg/kg and 200mg/kg in mice experimentally infected with a high parasite load of S. mansoni. Parasitological evaluations related to the number of S. mansoni worms and their oviposition were performed during the acute phase of the disease and have demonstrated moderate effectiveness of 30-54,4%. However, LPSF/PT-09 did not influence oviposition of the parasites or the embryonic development of the eggs. The results obtained in this model showed that the imidazolidine derivative LPSF/PT-09 presented significant antischistosomal activity in vivo, posing as a potential candidate for this class of drugs. However, a better understanding of the pharmacokinetics and pharmacodynamics of the imidazolidine derivative LPSF/PT-09 is needed.


Asunto(s)
Hidrazonas/farmacología , Imidazoles/farmacología , Esquistosomicidas/farmacología , Tiohidantoínas/farmacología , Animales , Colágeno/metabolismo , Hidrazonas/química , Imidazoles/química , Intestinos/efectos de los fármacos , Intestinos/parasitología , Hígado/efectos de los fármacos , Hígado/parasitología , Masculino , Ratones , Óvulo/efectos de los fármacos , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomiasis mansoni/parasitología , Esquistosomicidas/química , Tiohidantoínas/química
3.
Int J Biol Macromol ; 92: 467-475, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27435006

RESUMEN

Two new spiro-acridines were synthesized by introducing cyano-N-acylhydrazone between the acridine and phenyl rings followed by spontaneous cyclization. The final compounds (E)-1'-(benzylideneamino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-01) and (E)-1'-((4-methoxybenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-02) were evaluated for their interactions with calf thymus DNA, antiproliferative and human topoisomerase I and IIα inhibitory activities. Both compounds presented ability to bind DNA. The binding constant determined by UV-vis spectroscopy was found to be 104M-1. Antiproliferative assay demonstrated that AMTAC-01 and AMTAC-02 were most active against prostate and melanoma tumor cell lines, respectively. The compound did not present Topo I inhibitory activity. However, both derivatives displayed topoisomerase IIα inhibitory activity comparable to amsacrine, and AMTAC-02 was more potent than AMTAC-01 with methoxy substituent group on phenyl ring. This study demonstrates that the new derivatives are promising molecules with topoisomerase IIα inhibitory and antiproliferative activities.


Asunto(s)
Acridinas/farmacología , ADN-Topoisomerasas/metabolismo , ADN/metabolismo , Compuestos de Espiro/farmacología , Inhibidores de Topoisomerasa/farmacología , Acridinas/síntesis química , Acridinas/química , Animales , Espectroscopía de Resonancia Magnética con Carbono-13 , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química
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