Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against Leishmania tropica and L. infantum promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of Leishmania with IC50 values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one (14) and 9-(quinolizidinylmethylidene)fluorene (17), with selectivity index (SI) in the range 16–24, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of L. infantum. Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents.
Quinolizidine-derived lucanthone and amitriptyline analogues endowed with potent antileishmanial activity / M. Tonelli, A. Sparatore, N. Basilico, L. Cavicchini, S. Parapini, B. Tasso, E. Laurini, S. Pricl, V. Boido, F. Sparatore. - In: PHARMACEUTICALS. - ISSN 1424-8247. - 13:11(2020 Oct 25), pp. 339.1-339.17.
|Titolo:||Quinolizidine-derived lucanthone and amitriptyline analogues endowed with potent antileishmanial activity|
SPARATORE, ANNA CONCETTINA (Secondo) [Investigation] (Corresponding)
BASILICO, NICOLETTA [Investigation] (Corresponding)
CAVICCHINI, LOREDANA [Investigation]
|Parole Chiave:||Amitriptyline analogues; Antileishmanial agents; Leishmania tropica and infantum; Lucanthone analogues; Molecular modelling studies; Quinolizidine-derived compounds|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore MED/04 - Patologia Generale
|Data di pubblicazione:||25-ott-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/ph13110339|
|Appare nelle tipologie:||01 - Articolo su periodico|