title: Incorporation of basic side chains into cryptolepine scaffold: structure-antimalarial activity relationships and mechanistic studies.
abstract: The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon. Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Lavrado
authors.forename: Ghislain G
authors.initials: GG
authors.lastname: Cabal
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Cecília
authors.initials: C
authors.lastname: Díaz
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Daniel J V A
authors.initials: DJ
authors.lastname: dos Santos
authors.forename: Elena
authors.initials: E
authors.lastname: Bichenkova
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Douglas
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paulo
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002738:Chloroquine / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004351:Drug Resistance; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006427:Hemin / Q000737:chemistry; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015767:Mefloquine / Q000494:pharmacology; D009841:Oligonucleotides / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects; D011739:Pyrimethamine / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D026121:Indole Alkaloids; D009841:Oligonucleotides; D011804:Quinolines; C024015:cryptolepine; D006427:Hemin; D002738:Chloroquine; D004247:DNA; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3; D015767:Mefloquine; D011739:Pyrimethamine