title: Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.
abstract: 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.
authors: Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
authors: Bénédicte
authors: B
authors: Pacorel
authors: Suet C
authors: SC
authors: Leung
authors: Andrew V
authors: AV
authors: Stachulski
authors: Jill
authors: J
authors: Davies
authors: Livia
authors: L
authors: Vivas
authors: Hollie
authors: H
authors: Lander
authors: Stephen A
authors: SA
authors: Ward
authors: Marcel
authors: M
authors: Kaiser
authors: Reto
authors: R
authors: Brun
authors: Paul M
authors: PM
authors: O'Neill
mesh_terms: 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
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D009025:Morpholines; D010879:Piperazines; D011758:Pyrroles; D000077489:Piperazine; D002738:Chloroquine; C037574:morpholine