title: Peptidomimetic and organometallic derivatives of primaquine active against Leishmania infantum.
abstract: The current treatment of visceral leishmaniasis is made difficult by the low efficacy, elevated costs, low bioavailability, and high toxicity of many of the available drugs. Primaquine, an antimalarial 8-aminoquinoline, displays activity against Leishmania spp., and several of its derivatives have been developed as potential antileishmanial drugs. However, primaquine exhibits low oral bioavailability due to oxidative deamination of its aliphatic chain. We previously developed peptidomimetic and organometallic derivatives of primaquine, with higher resistance to proteolytic degradation and oxidative deamination, which presented significant activity against primaquine-sensitive pathogens such as Plasmodium or Pneumocystis. In light of these relevant findings, we decided to evaluate these compounds against both the promastigote and intramacrophagic amastigote forms of Leishmania infantum, the agent of Mediterranean visceral leishmaniasis. We found that several of these compounds had significant activity against L. infantum. One of the peptidomimetic (3c) and one of the organometallic (7a) derivatives of primaquine were active against the clinically relevant intramacrophagic amastigote form of the parasite, causing >96% reductions in the number of amastigotes per 100 macrophages at 60 and 40 μM, respectively, while being less cytotoxic for host cells than the reference drugs sitamaquine and miltefosine. Hence, compounds 3c and 7a represent new entries toward the development of new antileishmanial leads.
authors.affiliation: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Vale-Costa
authors.forename: Nuno
authors.initials: N
authors.lastname: Vale
authors.forename: Joana
authors.initials: J
authors.lastname: Matos
authors.forename: Ana
authors.initials: A
authors.lastname: Tomás
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
authors.forename: Maria Salomé
authors.initials: MS
authors.lastname: Gomes
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D020128:Inhibitory Concentration 50; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011319:Primaquine / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D057786:Peptidomimetics; D010767:Phosphorylcholine; C039128:miltefosine; D011319:Primaquine; C080436:8-aminoquinoline