title: Antileishmanial ring-substituted ether phospholipids.
abstract: 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. infantumand 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.
authors.affiliation: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece.
authors.forename: Nikos
authors.initials: N
authors.lastname: Avlonitis
authors.forename: Eleni
authors.initials: E
authors.lastname: Lekka
authors.forename: Anastasia
authors.initials: A
authors.lastname: Detsi
authors.forename: Maria
authors.initials: M
authors.lastname: Koufaki
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.forename: Efi
authors.initials: E
authors.lastname: Scoulica
authors.forename: Eleni
authors.initials: E
authors.lastname: Siapi
authors.forename: Ioanna
authors.initials: I
authors.lastname: Kyrikou
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: Andrew
authors.initials: A
authors.lastname: Tsotinis
authors.forename: Simona Golic
authors.initials: SG
authors.lastname: Grdadolnik
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D002152:Calorimetry, Differential Scanning; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004987:Ethers; D005434:Flow Cytometry; D007893:Leishmania donovani / Q000187:drug effects*; D018314:Leishmania infantum / Q000187:drug effects*; D008051:Lipid Bilayers / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010743:Phospholipids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004987:Ethers; D008051:Lipid Bilayers; D010743:Phospholipids; D014344:Trypanocidal Agents