Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.

Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Eduardo Sobarzo-Sánchez, Pablo Bilbao-Ramos, Maria Dea-Ayuela, Humberto González-Díaz, Matilde Yañez, Eugenio Uriarte, Lourdes Santana, Victoria Martínez-Sernández, Francisco Bolás-Fernández, Florencio M Ubeira
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/42d02becc0354f0b84780b4c633d05c4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:42d02becc0354f0b84780b4c633d05c4
record_format	dspace
spelling	oai:doaj.org-article:42d02becc0354f0b84780b4c633d05c42021-11-18T08:49:10ZSynthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.1932-620310.1371/journal.pone.0077560https://doaj.org/article/42d02becc0354f0b84780b4c633d05c42013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24204870/?tool=EBIhttps://doaj.org/toc/1932-6203Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).Eduardo Sobarzo-SánchezPablo Bilbao-RamosMaria Dea-AyuelaHumberto González-DíazMatilde YañezEugenio UriarteLourdes SantanaVictoria Martínez-SernándezFrancisco Bolás-FernándezFlorencio M UbeiraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e77560 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eduardo Sobarzo-Sánchez Pablo Bilbao-Ramos Maria Dea-Ayuela Humberto González-Díaz Matilde Yañez Eugenio Uriarte Lourdes Santana Victoria Martínez-Sernández Francisco Bolás-Fernández Florencio M Ubeira Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.
description	Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).
format	article
author	Eduardo Sobarzo-Sánchez Pablo Bilbao-Ramos Maria Dea-Ayuela Humberto González-Díaz Matilde Yañez Eugenio Uriarte Lourdes Santana Victoria Martínez-Sernández Francisco Bolás-Fernández Florencio M Ubeira
author_facet	Eduardo Sobarzo-Sánchez Pablo Bilbao-Ramos Maria Dea-Ayuela Humberto González-Díaz Matilde Yañez Eugenio Uriarte Lourdes Santana Victoria Martínez-Sernández Francisco Bolás-Fernández Florencio M Ubeira
author_sort	Eduardo Sobarzo-Sánchez
title	Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.
title_short	Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.
title_full	Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.
title_fullStr	Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.
title_full_unstemmed	Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.
title_sort	synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/42d02becc0354f0b84780b4c633d05c4
work_keys_str_mv	AT eduardosobarzosanchez syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT pablobilbaoramos syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT mariadeaayuela syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT humbertogonzalezdiaz syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT matildeyanez syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT eugeniouriarte syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT lourdessantana syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT victoriamartinezsernandez syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT franciscobolasfernandez syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities AT florenciomubeira syntheticoxoisoaporphinealkaloidsinvitroinvivoandinsilicoassessmentofantileishmanialactivities
_version_	1718421255890141184

Synthetic oxoisoaporphine alkaloids: in vitro, in vivo and in silico assessment of antileishmanial activities.

Ejemplares similares