ABSTRACT
SUMMARY Introduction: Leishmaniasis is a disease caused by protozoa of the genus Leishmania and is considered endemic in 98 countries. Treatment with pentavalent antimonials has a high toxicity, which motivates the search for effective and less toxic drugs. α- and β-lapachones have shown different biological activities, including antiprotozoa. In recent studies, the isonicotinoylhydrazone and phthalazinylhydrazone groups were considered innovative in the development of antileishmania drugs. Molecular hybridization is a strategy for the rational development of new prototypes, where the main compound is produced through the appropriate binding of pharmacophoric subunits. Aims: To synthesize four hybrids of α- and β-lapachones, together with the isonicotinoylhydrazone and phthalazinylhydrazone groups and to determine the antileishmania activity against the promastigotic forms of L. amazonensis, L. infantum and L. major. Results: β-lapachone derivatives were more active against all tested leishmania species. βACIL (IC50 0.044μM) and βHDZ (IC50 0.023μM) showed 15-fold higher activity than amphotericin B. The high selectivity index exhibited by the compounds indicates greater safety for vertebrate host cells. Conclusion: The results of this work show that the hybrids βACIL and (3HDZ are promising molecules for the development of new antileishmania drugs.
RESUMEN Introducción: Leishmaniasis es una enfermedad causada por protozoos del género Leishmania y se considera endémica en 98 países. El tratamiento con antimoniales pentavalentes tiene una alta toxicidad, lo que motiva la búsqueda de fármacos eficaces y menos tóxico. α- y β-lapachones han mostrado diferentes actividades biológicas, incluido los antiprotozoarios. En estudios recientes, los grupos isonicotinoilhidra-zona y ftalazinilhidrazona se consideraron innovadores en el desarrollo de fármacos antileishmania. La hibridación molecular es una estrategia para el desarrollo racional de nuevos prototipos, donde el compuesto principal se produce a través de la unión apropiada de subunidades farmacofóricas. Objetivos: Sintetizar cuatro híbridos de α- y β-lapachones, junto con los grupos isonicotinoilhidrazona y ftalazinilhidrazona y determinar la actividad antileishmania frente a las formas promastigotas de L. amazonensis, L. infantum y L. major. Resultados: Los derivados de β-lapachone fueron más activos contra todas las especies de leishmania probadas. La βACIL (CI50 0,044μM) y βHDZ (CI50 0,023μM) mostraron actividad 15 veces mayor que la anfotericina B. El alto índice de selectividad que presentan los compuestos indica una mayor seguridad para las células huésped del vertebrado. Conclusión: Los resultados de este trabajo demuestran que los híbridos (ACIL y (HDZ son moléculas prometodoras para el desarrollo de nuevos fármacos antileishmania.
RESUMO Introdução: A leishmaniose é uma doença causada por protozoários do género Leishmania e é considerada endémica em 98 países. O tratamento com antimoniais pentavalentes apresenta alta toxicidade, o que motiva a pesquisa por medicamentos eficazes e menos tóxicos. α- e β-lapachones tém mostrado diferentes atividades biológicas, incluindo antiprotozoários. Em estudos recentes, os grupos isonicotinoilhi-drazona e ftalazinilhidrazona foram considerados inovadores no desenvolvimento de drogas antileishmania. A hibridização molecular é uma estratégia para o desenvolvimento racional de novos protótipos, onde o composto principal é produzido através da ligação apropriada de subunidades farmacofóricas. Objetivos: Sintetizar quatro híbridos de α- e β-lapachones, juntamente com os grupos isonicotinoil-hidra-zona e ftalazinilhidrazona e determinar a atividade antileishmania contra as formas promastigóticas de L. amazonensis, L. infantum e L. major. Resultados: Os derivados de β-lapachona foram mais ativos contra todas as espécies de leishmania testadas. BACIL (IC50 0,044 μM) e βHDZ (IC50 0,023 μM) apresentaram atividade 15 vezes maior do que a anfotericina B. O alto índice de seletividade dos compostos indica maior segurança para células hospedeiras de vertebrados. Conclusaõ: Os resultados deste trabalho mostram que os híbridos βACIL e βHDZ são moléculas promissoras para o desenvolvimento de novos fármacos antileishmania.
ABSTRACT
The leishmaniases are severe parasitic diseases that occur worldwide, caused by protozoa of the genus Leishmania. Studies with medicinal plants can lead to a range of possibilities for treating and improving the patients' quality of life. Research on Azadirachta indica fractions and extracts has shown that they have excellent anti-leishmanial activity based on bioactivity-guided fractionation of ethanolic extracts of leaves and seeds and in vitro activity against promastigotes. In this research the most efficient extracts and fractions were selected for tests on intracellular amastigotes of Leishmania amazonensis. The ethanolic extract of the leaves and dichloromethane and chloroform fractions had IC50 values of 38, 3.9 and 1.2 μg/mL for promastigotes and 9.8, 1.1 and 0.6 μg/mL for amastigotes, respectively, at 72 hours. For the ethanolic extract and dichloromethane fraction from nut tegument, the IC50 was 2.7 and 2.1 μg/mL for promastigotes and 0.4 and 0.6 μg/mL for amastigotes. The cytotoxicity of the fractions presented selectivity that was between 8 to 32 times more toxic to promastigotes and 15 to 72 times to amastigotes than to macrophages. The extracts and fractions from leaves and fruits were more effective against amastigotes, and the fractionation increased activity against both promastigotes and amastigotes, enabling us to obtain potentially active fractions with low toxicity.