title: Pharmacomodulation on the 3-acetylursolic acid skeleton: Design, synthesis, and biological evaluation of novel N-{3-[4-(3-aminopropyl)piperazinyl]propyl}-3-O-acetylursolamide derivatives as antimalarial agents.
abstract: A series of new piperazine derivatives of ursolic acid was synthesized and tested against Plasmodium falciparum strains. They were also tested on their cytotoxicity effects upon MRC-5 cells. Seven new piperazinyl analogues showed significant activity in the nanomolar range (IC(50)=78-167nM) against Plasmodium falciparum CQ-resistant strain FcB1. A possible mechanism of interaction implicating binding of these compounds to beta-hematin was supported by in vitro tests. Moreover, the importance of the hydrophilic framework attached at the terminal nitrogen atom of the bis-(3-aminopropyl)piperazine joined to the triterpene ring was also explored through molecular dynamic simulations.
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Av. Ipiranga, 2752, Porto Alegre 90610-000, RS, Brazil.
authors.forename: Simone C B
authors.initials: SC
authors.lastname: Gnoatto
authors.forename: Sophie
authors.initials: S
authors.lastname: Susplugas
authors.forename: Luciana
authors.initials: L
authors.lastname: Dalla Vechia
authors.forename: Thais B
authors.initials: TB
authors.lastname: Ferreira
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dassonville-Klimpt
authors.forename: Karine R
authors.initials: KR
authors.lastname: Zimmer
authors.forename: Catherine
authors.initials: C
authors.lastname: Demailly
authors.forename: Sophie
authors.initials: S
authors.lastname: Da Nascimento
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
authors.forename: Hugo
authors.initials: H
authors.lastname: Verli
authors.forename: Grace
authors.initials: G
authors.lastname: Gosmann
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D030019:Ilex paraguariensis / Q000737:chemistry; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000097245:Ursolic Acid
chemical_list: D000962:Antimalarials; D010879:Piperazines; D014315:Triterpenes; D000097245:Ursolic Acid