Antileishmanial Ring-Substituted Ether Phospholipids

• Published in: Journal of medicinal chemistry Vol. 46; no. 5; pp. 755 - 767
• Main Authors: Avlonitis, Nikos, Lekka, Eleni, Detsi, Anastasia, Koufaki, Maria, Calogeropoulou, Theodora, Scoulica, Efi, Siapi, Eleni, Kyrikou, Ioanna, Mavromoustakos, Thomas, Tsotinis, Andrew, Grdadolnik, Simona Golic, Makriyannis, Alexandros
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27-02-2003
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Calorimetry, Differential Scanning; Cell Survival - drug effects; Cells, Cultured; Ethers; Flow Cytometry; Leishmania donovani - drug effects; Leishmania infantum - drug effects; Lipid Bilayers - chemistry; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Phospholipids - chemical synthesis; Phospholipids - chemistry; Phospholipids - pharmacology; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Kinetoplastida; Protozoa; Leishmania infantum; Cyclohexane derivatives; Ether; Aliphatic compound; Leishmania donovani; Phospholipid; Complex lipid; In vitro; Modeling; Antiprotozoal agent; Miltefosine; Structure activity relation; Parasiticid; Molecular model; Chemical synthesis; Promastigote
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020972c

Three series of ring-substituted ether phospholipids were synthesized carrying N,N,N-trimethylammonium, N-methylpiperidino, or N-methylmorpholino headgroups. The first series is substituted by 2-cyclohexyloxyethyl or 2-(4-alkylidenecyclohexyloxy)ethyl groups, the second series by cyclohexylidenealkyl or adamantylidenealkyl moieties, and the third series by 2-aryloxyethyl or 6-aryloxyhexyl groups in the alkyl portion of the molecule. The antileishmanial activity of the new compounds was evaluated in vitro against the promastigote forms of L. donovani and L. infantum using an MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide)-based microassay as a marker of cell viability. Analogues 12, 15, 24, 30, 32, 41, 43, and 45 were more potent than the control compound miltefosine (hexadecylphosphocholine) against both L. donovani and L. infantum while, derivatives 13 and 42 were equipotent to miltefosine. Analogues 16, 17, 19, 20 were more potent than miltefosine against L. infantum and compounds 27, 31, 44 were more active than miltefosine against L. donovani. Differential scanning calorimetry (DSC) was used to probe the role of individual ether phospholipids on the physicochemical properties of model membranes. The DSC scans showed that the active compounds have a more profound effect on the thermotropic properties of model membrane bilayers than the less active ones.