title: Leishmanicidal effects of piperine, its derivatives, and analogues on Leishmania amazonensis.
abstract: Leishmaniasis is a tropical disease caused by protozoan parasites of the genus Leishmania which affects 12 million people worldwide. The discovery of drugs for the treatment of leishmaniasis is a pressing concern in global health programs. The aim of this study aim was to evaluate the leishmanicidal effect of piperine and its derivatives/analogues on Leishmania amazonensis. Our results showed that piperine and phenylamide are active against promastigotes and amastigotes in infected macrophages. Both drugs induced mitochondrial swelling, loose kinetoplast DNA, and led to loss of mitochondrial membrane potential. The promastigote cell cycle was also affected with an increase in the G1 phase cells and a decrease in the S-phase cells, respectively, after piperine and phenylamide treatment. Lipid analysis of promastigotes showed that piperine reduced triglyceride, diacylglycerol, and monoacylglycerol contents, whereas phenylamide only reduced diacylglycerol levels. Both drugs were deemed non toxic to macrophages at 50 μM as assessed by XTT (sodium 2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt), Trypan blue exclusion, and phagocytosis assays, whereas low toxicity was noted at concentrations higher than 150 μM. None of the drugs induced nitric oxide (NO) production. By contrast, piperine reduced NO production in activated macrophages. The isobologram analysis showed that piperine and phenylamide acted synergistically on the parasites suggesting that they affect different target mechanisms. These results indicate that piperine and its phenylamide analogue are candidates for development of drugs for cutaneous leishmaniasis treatment.
authors: Instituto de Veterinária, Universidade Federal Rural do Rio de Janeiro (UFRRJ), Seropédica, RJ, Brazil.
authors: C
authors: C
authors: Ferreira
authors: D C
authors: DC
authors: Soares
authors: C B
authors: CB
authors: Barreto-Junior
authors: M T
authors: MT
authors: Nascimento
authors: L
authors: L
authors: Freire-de-Lima
authors: J C
authors: JC
authors: Delorenzi
authors: M E F
authors: ME
authors: Lima
authors: G C
authors: GC
authors: Atella
authors: E
authors: E
authors: Folly
authors: T M U
authors: TM
authors: Carvalho
authors: E M
authors: EM
authors: Saraiva
authors: L H
authors: LH
authors: Pinto-da-Silva
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D005638:Fruit; D005989:Glycerides / Q000378:metabolism; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D050356:Lipid Metabolism / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology; D008928:Mitochondria / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D008517:Phytotherapy; D031701:Piper / Q000737:chemistry*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000494:pharmacology / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000470:Alkaloids; D000577:Amides; D052117:Benzodioxoles; D005989:Glycerides; D010880:Piperidines; D010936:Plant Extracts; D053284:Polyunsaturated Alkamides; D014344:Trypanocidal Agents; D009569:Nitric Oxide; C008922:piperine