Subject(s)
Antimalarials/chemistry , Spiro Compounds/chemistry , Tetraoxanes/chemistry , Alkylation , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Artemisinins/chemical synthesis , Artemisinins/chemistry , Artemisinins/pharmacology , Drug Resistance, Multiple , Plasmodium falciparum/drug effects , Plasmodium falciparum/isolation & purification , Small Molecule Libraries/chemistry , Spiro Compounds/chemical synthesis , Tetraoxanes/chemical synthesis , Tetraoxanes/pharmacologyABSTRACT
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.
Subject(s)
Antimalarials/chemical synthesis , Artemisinins/pharmacology , Pyrroles/chemistry , Antimalarials/pharmacology , Artemisinins/chemical synthesis , Chloroquine/pharmacology , Drug Resistance , Inhibitory Concentration 50 , Morpholines , Piperazine , Piperazines , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.