Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.
In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.
Pacorel
Bénédicte
B
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Leung
Suet C
SC
Stachulski
Andrew V
AV
Davies
Jill
J
Vivas
Livia
L
Lander
Hollie
H
Ward
Stephen A
SA
Kaiser
Marcel
M
Brun
Reto
R
O'Neill
Paul M
PM
D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D020128:Inhibitory Concentration 50; D009025:Morpholines; D000077489:Piperazine; D010879:Piperazines; D010963:Plasmodium falciparum / Q000187:drug effects; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D037621:Artemisinins; D009025:Morpholines; D010879:Piperazines; D011758:Pyrroles; D000077489:Piperazine; D002738:Chloroquine; C037574:morpholine