ABSTRACT
OBJECTIVES: This paper describes the antileishmanial properties of LQB-118, a new compound designed by molecular hybridization, orally active in Leishmania amazonensis-infected BALB/c mice. METHODS: In vitro antileishmanial activity was determined in L. amazonensis-infected macrophages. For in vivo studies, LQB-118 was administered intralesionally (15 µg/kg/day, five times a week), intraperitoneally (4.5 mg/kg/day, five times a week) or orally (4.5 mg/kg/day, five times a week) to L. amazonensis-infected BALB/c mice throughout experiments lasting 85 or 105 days. At the end of the experiments, serum levels of alanine aminotransferase, aspartate aminotransferase and creatinine were measured as toxicological parameters. RESULTS: LQB-118 was active against intracellular amastigotes of L. amazonensis [50% inhibitory concentration (IC(50)) 1.4 µM] and significantly less so against macrophages (IC(50) 18.5 µM). LQB-118 administered intralesionally, intraperitoneally or orally was found to control both lesion and parasite growth in L. amazonensis-infected BALB/c mice, without altering serological markers of toxicity. CONCLUSIONS: These results demonstrate that the molecular hybridization of a naphthoquinone core to pterocarpan yielded a novel antileishmanial compound that was locally and orally active in an experimental cutaneous leishmaniasis model.
Subject(s)
Antiprotozoal Agents/administration & dosage , Leishmaniasis, Cutaneous/drug therapy , Administration, Oral , Administration, Topical , Alanine Transaminase/blood , Animals , Antiprotozoal Agents/adverse effects , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Aspartate Aminotransferases/blood , Chemical and Drug Induced Liver Injury/diagnosis , Creatinine/blood , Disease Models, Animal , Inhibitory Concentration 50 , Leishmania mexicana/drug effects , Leishmaniasis, Cutaneous/parasitology , Liver/enzymology , Mice , Mice, Inbred BALB C , Naphthoquinones/administration & dosage , Naphthoquinones/adverse effects , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Pterocarpans/administration & dosage , Pterocarpans/adverse effects , Pterocarpans/chemistry , Pterocarpans/pharmacology , Rodent Diseases/drug therapy , Rodent Diseases/parasitology , Serum/chemistry , Treatment OutcomeABSTRACT
In a previous works searching for new drugs with high efficiency, we reported the in vitro and in vivo antileishmanial activity of a series of diarylheptanoid structurally related to curcumin against L. amazonensis. This work describes the in vitro antileishmanial activity of a new series of diarylheptanoids and diarylpentanoids derivatives. These drugs were assayed against Leishmania amazonensis, L. braziliensis and L. chagasi promastigotes containing a high percentage of metacyclic forms and the axenic amastigote form of L. amazonensis and using Pentamidine Isethionate as reference drug. Parasites in the log late phase culture were incubated with several concentrations of the drugs solubilized in dimethyl sulphoxide (DMSO) and then counted in a Neubauer's chamber. Controls without the drugs and with DMSO were done in parallel. The results showed that all diarylheptanoids and diarylpentanoids had a very good antileishmanial activity.
