Mode of action of p-quinone derivatives with trypanocidal activity studied by experimental and<i> in</i><i> silico</i> models

Simple item page
dc.contributor.authorBallesteros-Casallas, Andres
dc.contributor.authorQuiroga, Cristina
dc.contributor.authorOrtiz, Cecilia
dc.contributor.authorBenitez, Diego
dc.contributor.authorDenis, Pablo A.
dc.contributor.authorFigueroa, David
dc.contributor.authorSalas, Cristian O.
dc.contributor.authorBertrand, Jeanluc
dc.contributor.authorTapia, Ricardo A.
dc.contributor.authorSanchez, Patricio
dc.contributor.authorMiscione, Gian Pietro
dc.contributor.authorComini, Marcelo A.
dc.contributor.authorPaulino, Margot
dc.date.accessioned2025-01-20T20:19:55Z
dc.date.available2025-01-20T20:19:55Z
dc.date.issued2023
dc.description.abstractQuinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis.The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC50=38 mu M), proved to be similarly or even more potent (EC50 = 0.5-5.5 mu M) than the clinical drug nifurtimox (EC50 = 5.3 mu M). Three furanequinones and one thia-zolequinone displayed a higher selectivity than nifurtimox. Two of these selective hits resulted potent inhibitors of T. cruzi proliferation (EC50=0.8-1.1 mu M) but proved inactive against Leishmania infantum amastigotes.Most of the p-quinones induced a rapid and marked intracellular oxidation in T. b. brucei. DFT calculations on the oxidized quinone (Q), semiquinone (Q center dot-) and hydroquinone (QH2) suggest that all quinones have negative Delta G for the formation of Q center dot-. Qualitative and quantitative structure-activity relationship analyses in two or three dimensions of different electronic and biophysical descriptors of quinones and their corresponding bioactivities (killing potency and oxidative capacity) were performed.Charge distribution over the quinone ring carbons of Q and Q.-and the frontier orbitals energies of SUMO (Q.-) and LUMO (Q) correlate with their oxidative and trypanocidal activity. QSAR analysis also highlighted that both bromine substitution in the p-quinone ring and a bulky phenyl group attached to the furane and thiazole rings (which generates a negative charge due to the 7C electron system polarized by the nearby heteroatoms) are favorable for activity.By combining experimental and in silico procedures, this study disclosed important information about p-qui-nones that may help to rationally tune their electronic properties and biological activities.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.ejmech.2022.114926
dc.identifier.eissn1768-3254
dc.identifier.issn0223-5234
dc.identifier.urihttps://doi.org/10.1016/j.ejmech.2022.114926
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92551
dc.identifier.wosidWOS:000902004200005
dc.language.isoen
dc.revistaEuropean journal of medicinal chemistry
dc.rightsacceso restringido
dc.subjectGenetically-encoded redox biosensor
dc.subjectLeishmania
dc.subjectp-Quinones
dc.subjectQSAR
dc.subjectRedox cycling
dc.subjectThiol-redox balance
dc.subjectTrypanosoma
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleMode of action of p-quinone derivatives with trypanocidal activity studied by experimental and<i> in</i><i> silico</i> models
dc.typeartículo
dc.volumen246
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
Files
Collections
Artículos de revistas