title: Synthesis and antiprotozoal activity of N-alkoxy analogues of the trypanocidal lead compound 4,4'-bis(imidazolinylamino)diphenylamine with improved human blood-brain barrier permeability.
abstract: To improve the blood-brain barrier permeability of the trypanocidal lead compound 4,4'-bis(imidazolinylamino)diphenylamine (1), five N-alkoxy analogues were synthesized from bis(4-isothiocyanatophenyl)amine and N-alkoxy-N-(2-aminoethyl)-2-nitrobenzenesulfonamides following successive chemical reactions in just one reactor ("one-pot procedure"). This involved: (a) formation of a thiourea intermediate, (b) removal of the amine protecting groups, and (c) intramolecular cyclization. The blood-brain barrier permeability of the compounds determined in vitro by transport assays through the hCMEC/D3 human cell line, a well-known and characterized human cellular blood-brain barrier model, showed that the N-hydroxy analogue 16 had enhanced blood-brain barrier permeability compared with the unsubstituted lead compound. Moreover, this compound displayed low micromolar IC(50) against Trypanosoma brucei rhodesiense and Plasmodium falciparum and moderate activity by intraperitoneal administration in the STIB900 murine model of acute sleeping sickness.
authors.affiliation: Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Nieto
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mascaraque
authors.forename: Florence
authors.initials: F
authors.lastname: Miller
authors.forename: Fabienne
authors.initials: F
authors.lastname: Glacial
authors.forename: Carlos
authors.initials: C
authors.lastname: Ríos Martínez
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardonville
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014347:Trypanosoma brucei gambiense; D014349:Trypanosoma cruzi / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000962:Antimalarials; D048288:Imidazolines; D014344:Trypanocidal Agents; D004159:Diphenylamine