Reversal of chloroquine resistance in Plasmodium falciparum by 9H-xanthene derivatives.
Four new chemosensitisers against chloroquine-resistant Plasmodium falciparum based on the 9H-xanthene tricyclic scaffold were designed and synthesised in an attempt to identify simplified compounds that are easily accessible from commercially available starting materials. The compounds contain a common hydrophobic tricyclic 9H-xanthene moiety and an alkyl side chain with two amino groups, one of which is a tertiary substituted terminal amine, separated by three carbons and differing only in the chemical nature of the intermediary nitrogen atom. The best chemosensitising compound has a secondary amino group, showed a response modification index of 0.36 and caused a four-fold increase in chloroquine accumulation in a resistant strain of P. falciparum as well as having the highest selective therapeutic index when tested against a mammalian cell line.
Wu
Chung-Pu
CP
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
van Schalkwyk
Donelly A
DA
Taylor
Dale
D
Smith
Peter J
PJ
Chibale
Kelly
K
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D016466:CHO Cells; D002738:Chloroquine / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity*; D006224:Cricetinae; D004347:Drug Interactions; D004351:Drug Resistance / Q000187:drug effects*; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects*; D014966:Xanthenes / Q000737:chemistry* / Q000494:pharmacology
D000962:Antimalarials; D014966:Xanthenes; D002738:Chloroquine