Antileishmanial activity of polycyclic derivatives
M E Sarciron1, R Terreux, Y Prieto
1Department of Parasitology and Medical Mycology, EA3741, Claude Bernard University, Lyon, France. sarciron@univ-lyon1.fr
Parasite (Paris, France)
|October 13, 2005
Summary
New polycyclic compounds show potent antileishmanial activity against Leishmania parasites. Many derivatives are more effective than amphotericin B and exhibit lower toxicity to human cells.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Leishmaniasis remains a significant global health concern, necessitating novel therapeutic agents.
- Existing treatments like amphotericin B and pentamidine have limitations, including toxicity and resistance.
- Polycyclic compounds represent a promising scaffold for developing new antileishmanial drugs.
Purpose of the Study:
- To synthesize and evaluate the antileishmanial activity of 33 novel polycyclic derivatives.
- To assess the in vitro cytotoxicity of these derivatives against a human myelomonocytic cell line.
- To establish structure-activity relationships (SAR) and guide future drug optimization using 3D QSAR.
Main Methods:
- Synthesis of 33 polycyclic derivatives.
- In vitro assessment of antileishmanial activity against Leishmania donovani and Leishmania major promastigotes.
- Cytotoxicity evaluation on the human THP-1 cell line.
- 3D Quantitative Structure-Activity Relationship (QSAR) modeling.
Main Results:
- 29 out of 33 derivatives demonstrated antileishmanial activity.
- 25 derivatives were more potent against Leishmania donovani than amphotericin B.
- Nine derivatives showed comparable efficacy to amphotericin B against Leishmania major.
- 12 derivatives exhibited similar cytotoxicity to reference drugs, while 21 were significantly less toxic.
- 3D QSAR analysis identified key structural features for optimizing activity against both Leishmania species.
Conclusions:
- Several novel polycyclic derivatives possess significant antileishmanial potential with favorable safety profiles.
- The synthesized compounds offer promising leads for developing new treatments for leishmaniasis.
- 3D QSAR provides valuable insights for the rational design of more effective and safer antileishmanial agents.
More Related Videos
08:48Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation
Published on: January 26, 2016
12:02An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity
Published on: November 2, 2016
Related Concept Videos
01:26Physical Properties of Amines
Amines with low molecular weight are usually gaseous at room temperature, while those with high molecular weight are liquid or solids in nature. Usually, low molecular weight amines have a rotten fish-like smell. Diamines typically have a pungent smell. For instance, cadaverine and putrescine, depicted in Figure 1, are two molecules responsible for decaying tissue.
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
01:30Leishmaniasis
Leishmaniasis is a protozoal disease caused by species of the genus Leishmania and transmitted through the bite of infected female sandflies. The parasite exists in two principal morphological forms during its life cycle. A sandfly acquires intracellular amastigotes from an infected reservoir host, such as a dog. Within the sandfly, these forms differentiate into motile, flagellated promastigotes. During a subsequent blood meal, promastigotes are injected into the human host, where they...
01:15Antifungal Agents
Amphotericin B is a broad-spectrum antifungal agent that exploits structural differences between fungal and mammalian cell membranes. Its amphipathic structure—featuring a hydrophobic polyene-lactone ring and a hydrophilic region containing mycosamine and carboxylic acid groups—enables selective binding to ergosterol, a sterol predominantly found in fungal plasma membranes. This selective interaction underlies the drug’s antifungal activity, although weak binding to cholesterol contributes to...
01:15Anthelminthic Agents
Anthelmintic drugs differ significantly from antiparasitic therapies targeting protozoa, primarily due to differences in parasite biology. Whereas most protozoal treatments act on proliferating cells, anthelmintics are typically directed against mature, nonproliferative helminths. The therapeutic approach considers the helminth's reliance on neuromuscular coordination, glucose metabolism, and microtubular integrity for survival, reproduction, and localization within the host. Most anthelmintics...
01:21Antiprotozoal Agents
Leishmaniasis is a widespread parasitic disease caused by several Leishmania species. It affects millions of people each year and remains a major public health problem in endemic regions. First-line treatment relies on pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate. Even so, how these drugs work has not been fully clear, especially their interaction with parasite-specific biochemical pathways. One key target is trypanothione reductase (TR), an enzyme that...