ABSTRACT
Artesunic acid 5, the hemisuccinate derivative of dihydroartemisinin 2, is the only clinically useful water-soluble derivative of artemisinin 1. However, being a lactol ester, it is rapidly hydrolyzed back to dihydroartemisinin in aqueous alkaline solution, a reaction that seriously limits its utility. A new series of potentially more stable linker-based hemisuccinate derivatives 12a-i and 14a-c have been prepared. The process involved acid-catalyzed reaction of dihydroartemisinin with various diols and polyethylene glycols to give hydroxy-functionalized ethers 7a-i and 10a-c and their further derivatization to hemisuccinate esters 12a-i and 14a-c. Both the hydroxy-functionalized ethers 7a-i and 10a-c and their hemisuccinate derivatives 12a-i and 14a-c have been assessed for antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. Several of these hemisuccinate derivatives have shown very promising activity. Hemisuccinate derivatives 12f and 12i, the two most active compounds of the series, provided 100% protection to malaria-infected mice at 24 mg/kg × 4 days and therefore are twice as potent as artesunic acid, which provides a similar level of protection at 48 mg/kg × 4 days.
Subject(s)
Antimalarials/chemical synthesis , Artemisinins/chemical synthesis , Drug Resistance, Multiple , Malaria/prevention & control , Plasmodium yoelii/drug effects , Succinates/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Artemisinins/chemistry , Artemisinins/pharmacology , Malaria/parasitology , Mice , Schizonts/drug effects , Structure-Activity Relationship , Succinates/chemistry , Succinates/pharmacologyABSTRACT
A highly efficient route for the conversion of the antimalarial drug artemisinin to a novel hydroxy-functionalized tricyclic 1,2,4-trioxane 6 is reported. Neither the trioxane 6 nor its derivatives 14-16, all of which lack the hydrolytically unstable acetal-lactone linkage, show antimalarial activity comparable with that of artemisinin.
Subject(s)
Antimalarials/chemistry , Artemisinins/chemistry , Heterocyclic Compounds/chemical synthesis , Antimalarials/pharmacology , Artemisinins/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
New 6-arylvinyl- and 6-adamantylvinyl-substituted 1,2,4-trioxanes (13a-g and 14a,b) have been prepared and evaluated for antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular routes. While all the 6-arylvinyl-substituted trioxanes, 13a-f, showed promising activity, none of the 6-adamantylvinyl-substituted trioxanes, 13g and 14a,b, exhibited significant activity. Trioxane, 13f, the most active compound of the series, provided 100% and 80% protection to malaria-infected mice at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively, by oral route. In this model, beta-arteether (3) provided 100% protection at 48 mg/kg x 4 days and only 20% protection at 24 mg/kg x 4 days. Trioxane 13f also showed complete suppression of parasitaemia at 10 mg/kg x 4 days by oral route in rhesus monkeys infected with P. cynomolgi. None of these trioxanes, except 13f, showed significant activity by the intramuscular route.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Antimalarials/chemical synthesis , Heterocyclic Compounds, 1-Ring/chemical synthesis , Malaria/drug therapy , Spiro Compounds/chemical synthesis , Adamantane/pharmacology , Administration, Oral , Animals , Antimalarials/pharmacology , Drug Resistance , Heterocyclic Compounds, 1-Ring/pharmacology , Injections, Intramuscular , Macaca mulatta , Malaria/parasitology , Mice , Parasitemia/drug therapy , Parasitemia/parasitology , Plasmodium cynomolgi/drug effects , Plasmodium yoelii/drug effects , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
A new series of 8-(1-aryl-vinyl)-6,7,10-trioxaspiro [4.5] decanes 7a-e and 3-(1-aryl-vinyl)-l,2,5-trioxaspiro [5.5] undecanes 8a-e have been prepared and screened against multi-drug resistant Plasmodium yoelii in mice. 8-(1-Naphthalen-2-yl-vinyl)-6,7,10-trioxaspiro [4.5] decane 7b, the most active trioxane of the series, has also shown promising activity against Plasmodium cynomolgi in rhesus monkeys.
