piperidines and Leishmaniasis

Leishmaniasis is one of the most important neglected tropical diseases (NTDs) that are especially common among low-income populations in developing regions of Africa, Asia, and the Americas. Many natural products, particularly alkaloids, have been reported to have inhibitory activity against arginase, the key enzyme in the pathology caused by Leishmania sp. In this way, piperidine alkaloids (-)-cassine (1), (-)-spectaline (2), (-)-3-O-acetylcassine (3), and (-)-3-O-acetylspectaline (4) were isolated from Senna spectabilis flowers. These compounds (1/2 and 3/4) initially present as homologous mixtures were separated by high performance liquid chromatography and evaluated against the promastigote phase of Leishmania amazonensis. In addition, molecular docking simulations were implemented in order to probe the binding modes of the ligands 1-4 to the amino acids in the active site of L. amazonensis arginase. Alkaloid 2 (IC

Topics: Alkaloids; Antiprotozoal Agents; Dose-Response Relationship, Drug; Leishmania; Leishmaniasis; Molecular Docking Simulation; Molecular Structure; Parasitic Sensitivity Tests; Piperidines; Senna Plant; Structure-Activity Relationship

FT-IR spectrum of (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-1-one was recorded and analyzed. The vibrational wavenumbers were computed using HF and DFT quantum chemical calculations. The data obtained from wavenumber calculations are used to assign IR bands. Potential energy distribution was done using GAR2PED software. The geometrical parameters of the title compound are in agreement with the XRD results. NBO analysis, HOMO-LUMO, first and second hyperpolarizability and molecular electrostatic potential results are also reported. The possible electrophile attacking sites of the title molecule is identified using MEP surface plot study. Molecular docking results predicted the anti-leishmanic activity for the compound.

Topics: Antiprotozoal Agents; Drug Discovery; Humans; Leishmania; Leishmaniasis; Molecular Docking Simulation; Nitro Compounds; Piperidines; Spectroscopy, Fourier Transform Infrared; Static Electricity

Senna spectabilis (sin. Cassia excelsa, C. spectabilis) is an endemic tree of South America and Africa, very common in Brazil, where it is known as "canafistula-de-besouro" and "cassia-do-nordeste". In folk medicine, this plant is indicated for the treatment of constipation, insomnia, anxiety, epilepsy, malaria, dysentery and headache. Phytopharmacological studies have also confirmed anticonvulsive, sedative, anti-malarial, antimicrobial and cytotoxic properties of many parts of S. spectabilis. In this communication, we present a comparative study of the leishmanicidal activity of the crude ethanolic extract, its fractions and also the two major alkaloidal metabolites (-)-cassine/(-)-spectaline, trying to establish a relationship between the presence of piperidine alkaloidal constituents and leishmanicidal activity. The growth inhibitory effect of promastigote forms of Leishmania major was determined for the crude extract, fractions of the flowers of S. spectabilis and a mixture of (-)-cassine/(-)-spectaline in comparison to pentamidine used as standard drug. The cytotoxic effects were assessed on macrophage strain J774 by lactate dehydrogenase assay. Fractions dichloromethane (FL-DCM) and n-butanol (FL-Bu) and a mixture of (-)-cassine/(-)-spectaline (∼7:3) exhibited significant activity against the parasite Leishmania major (IC50 values of 0.6±0.1 μg/ml, 1.6±0.9 μg/ml and 24.9±1.4 μg/ml, respectively), without toxic effects on murine macrophages. Due to the promising results elicited, further studies in vivo need to be performed to confirm the therapeutic potential of Senna spectabilis.

Topics: Antiparasitic Agents; Flowers; Ketones; Leishmania major; Leishmaniasis; Life Cycle Stages; Medicine, Traditional; Pentamidine; Piperidines; Plant Extracts; Senna Plant

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.

Topics: Alkaloids; Amides; Benzodioxoles; Cell Cycle; Fruit; Glycerides; Leishmania; Leishmaniasis; Leishmaniasis, Cutaneous; Lipid Metabolism; Macrophages; Mitochondria; Nitric Oxide; Phytotherapy; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Trypanocidal Agents

Based on reported antileishmanial activity of naturally occurring alkaloid piperine and amino acid esters, their conjugates were synthesized by the hydrolysis of piperine to piperic acid followed by reaction with amino acid methyl esters. These conjugates were further converted to compounds with free carboxyl group and those with reduced double bonds. The synthesized compounds were evaluated for activity against promastigote and amastigote forms of L. donovani in vitro. All the compounds showed better activity than either piperine or the amino acid methyl esters. Piperoyl-valine methyl ester was the most active compound showing an IC50 of 0.075 mM against the amastigotes. Two active compounds were evaluated for in vivo activity in golden hamster model of leishmaniasis.

Topics: Alkaloids; Amino Acids; Animals; Antiprotozoal Agents; Benzodioxoles; Catalytic Domain; Cricetinae; Esters; Humans; Inhibitory Concentration 50; Leishmania donovani; Leishmaniasis; Male; Models, Molecular; Piperidines; Polyunsaturated Alkamides