title: In search of novel agents for therapy of tropical diseases and human immunodeficiency virus.
abstract: Malaria, sleeping sickness, Chagas' disease, Aleppo boil, and AIDS are among the tropical diseases causing millions of infections and cases of deaths per year because only inefficient chemotherapy is available. Since the targeting of the enzymes of the polyamine pathway may provide novel therapy options, we aimed to inhibit the deoxyhypusine hydroxylase, which is an important step in the biosynthesis of the eukaryotic initiation factor 5A. In order to identify new lead compounds, piperidines were produced and biologically evaluated. The 3,5-diethyl piperidone-3,5-dicarboxylates 11 and 13 substituted with 4-nitrophenyl rings in the 2 and 6 positions were found to be active against Trypanosoma brucei brucei and Plasmodium falciparum combined with low cytotoxicity against macrophages. The corresponding monocarboxylates are only highly active against the T. brucei brucei. The piperidine oximether 53 demonstrated the highest plasmodicidal activity. Moreover, compounds 11 and 53 were also able to inhibit replication of HIV-1.
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Goebel
authors.forename: Daniela
authors.initials: D
authors.lastname: Ulmer
authors.forename: Holger
authors.initials: H
authors.lastname: Projahn
authors.forename: Jessica
authors.initials: J
authors.lastname: Kloeckner
authors.forename: Eberhard
authors.initials: E
authors.lastname: Heller
authors.forename: Melanie
authors.initials: M
authors.lastname: Glaser
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.forename: Sabine
authors.initials: S
authors.lastname: Specht
authors.forename: Salem Ramadan
authors.initials: SR
authors.lastname: Sarite
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.forename: Annette
authors.initials: A
authors.lastname: Kaiser
authors.forename: Ilona
authors.initials: I
authors.lastname: Hauber
authors.forename: Joachim
authors.initials: J
authors.lastname: Hauber
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D018320:Leishmania major / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000962:Antimalarials; D004987:Ethers; D010091:Oximes; D010880:Piperidines; D013141:Spiro Compounds; D014344:Trypanocidal Agents