Structure-activity relationships and mechanistic studies of novel mitochondria-targeted, leishmanicidal derivatives of the 4-aminostyrylquinoline scaffold

• DOI: 10.1016/j.ejmech.2019.03.007
• Publication Date: 2019-03-14T06:18:03Z
• Authors: Matteo Staderini; Marta Piquero; María Ángeles Abe...; Montserrat Nachér...; Giulia Romanelli; Pilar López-Alvarado; Luis Rivas; Maria Laura Bolog...; J. Carlos Menéndez
• Keywords: Leishmania; Microscopy, Confocal; Dose-Response Relationship, Drug; Molecular Structure; Antiprotozoal Agents; 4-Aminoquinolines; Leishmanicidal compounds; Mitochondria; Structure-Activity Relationship; 03 medical and health sciences; 0302 clinical medicine; Parasitic Sensitivity Tests; Mitochondrial metabolism; Quinolines; 2-Styrylquinolines; 2-Styrylquinolines; 4-Aminoquinolines; Leishmanicidal compounds; Mitochondrial metabolism; Antiprotozoal Agents; Dose-Response Relationship, Drug; Leishmania; Microscopy, Confocal; Mitochondria; Molecular Structure; Parasitic Sensitivity Tests; Quinolines; Structure-Activity Relationship

A new class of quinoline derivatives, bearing amino chains at C-4 and a styryl group at C-2, were tested on Leishmania donovani promastigotes and axenic and intracellular Leishmania pifanoi amastigotes. The introduction of the C-4 substituent improves the activity, which is due to interference with the mitochondrial activity of the parasite and its concomitant bioenergetic collapse by ATP exhaustion. Some compounds show a promising antileishmanial profile, with low micromolar or submicromolar activity on promastigote and amastigote forms and a good selectivity index.