title: Mechanisms of action of substituted β-amino alkanols on Leishmania donovani.
abstract: Leishmaniasis is the protozoan disease second in importance for human health, superseded only by malaria; however, the options for chemotherapeutic treatment are increasingly limited due to drug resistance and toxicity. Under this perspective, a quest for new chemical compounds is urgently needed. An N-substituted 2-aminoalkan-1-ol scaffold has been shown to be a versatile scaffold for antiparasitic activity. Knowledge about its mechanism of action is still rather limited. In this work, we endeavored to define the leishmanicidal profile of such β-amino alkanol derivatives using a set of 15 N-mono- and disubstituted surrogates, tested on Leishmania donovani promastigotes and intracellular amastigotes. The best compound (compound 5), 2-ethylaminododecan-1-ol, had a 50% effective concentration (EC50) of 0.3 μM and a selectivity index of 72 for infected THP-1 cells and was selected for further elucidation of its leishmanicidal mechanism. It induced fast depletion of intracellular ATP content in promastigotes in the absence of vital dye intracellular entry, ruling out plasma membrane permeabilization as its origin. Confocal and transmission electron microscopy analyses showed that compound 5 induced severe mitochondrial swelling and vesiculation. Polarographic analysis using an oxygen electrode demonstrated that complex II of the respiratory chain (succinate reductase) was strongly inhibited by compound 5, identifying this complex as one of the primary targets. Furthermore, for other β-amino alkanols whose structures differed subtly from that of compound 5, plasma membrane permeabilization or interference with membrane traffic was also observed. In all, N-substituted β-amino alkanols were shown as appealing leishmanicidal candidates deserving further exploration.
authors.affiliation: Centro de Investigaciones Biológicas (CIB-CSIC), Unidad Metabolómica, Interacciones y Bioanálisis (UMIB), Madrid, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Abengózar
authors.affiliation: Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain Departamento de Ciencias Farmacéuticas, Facultad de Ciencias, Universidad Católica del Norte, Antofagasta, Chile.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Bustos
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), Granada, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: García-Hernández
authors.affiliation: Centro de Investigaciones Biológicas (CIB-CSIC), Unidad Metabolómica, Interacciones y Bioanálisis (UMIB), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Fernández de Palencia
authors.affiliation: Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Escarcena
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), Granada, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.affiliation: Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: del Olmo
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.affiliation: Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: San Feliciano
authors.affiliation: Centro de Investigaciones Biológicas (CIB-CSIC), Unidad Metabolómica, Interacciones y Bioanálisis (UMIB), Madrid, Spain luis.rivas@cib.csic.es.
authors.forename: Luis
authors.initials: L
authors.lastname: Rivas
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000648:ultrastructure; D015394:Molecular Structure; D010101:Oxygen Consumption / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents