Synthesis and antileishmanial activity of C7- and C12-functionalized dehydroabietylamine derivatives.
Abietane-type diterpenoids, either naturally occurring or synthetic, have shown a wide range of pharmacological actions, including antiprotozoal properties. In this study, we report on the antileishmanial evaluation of a series of (+)-dehydroabietylamine derivatives functionalized at C7 and/or C12. Thus, the activity in vitro against Leishmania infantum, Leishmania donovani, Leishmania amazonensis and Leishmania guyanensis, was studied. Most of the benzamide derivatives showed activities at low micromolar concentration against cultured promastigotes of Leishmania spp. (IC50 = 2.2-46.8 μM), without cytotoxicity on J774 macrophage cells. Compound 15, an acetamide, was found to be the most active leishmanicidal agent, though it presented some cytotoxicity on J774 cells. Among the benzamide derivatives, compounds 8 and 10, were also active against L. infantum intracellular amastigotes, being 18- and 23-fold more potent than the reference compound miltefosine, respectively. Some structure-activity relationships have been identified for the antileishmanial activity in these dehydroabietylamine derivatives.
Departamento de Farmacia, Universidad CEU Cardenal Herrera, Avda. Seminario s/n, 46113 Moncada (Valencia), Spain; Departamento de Parasitología, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
M Auxiliadora
MA
Dea-Ayuela
Departamento de Parasitología, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
Pablo
P
Bilbao-Ramos
Departamento de Parasitología, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
Francisco
F
Bolás-Fernández
Instituto de Tecnología Química, Universitat Politècnica de València-Consejo Superior de Investigaciones Científicas, Avda. de los Naranjos s/n, 46022 Valencia, Spain. Electronic address: migoncar@itq.upv.es.
Miguel A
MA
González-Cardenete
D045784:Abietanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects; D007893:Leishmania donovani / Q000187:drug effects*; D018314:Leishmania infantum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D045784:Abietanes; D000981:Antiprotozoal Agents; C000600819:dehydroabietylamine
Abietane; Dehydroabietylamine; Diterpene; Leishmanicidal