Antimalarial Simplified 3-Aryltrioxanes:  Synthesis and Preclinical Efficacy/Toxicity Testing in Rodents

• Published in: Journal of medicinal chemistry 2001-09, Vol.44 (19), p.3054-3058
• Main Authors: Posner, Gary H, Jeon, Heung Bae, Parker, Michael H, Krasavin, Mikhail, Paik, Ik-Hyeon, Shapiro, Theresa A
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antimalarials - toxicity; Antiparasitic agents; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Benzoates - toxicity; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - toxicity; Drug Evaluation, Preclinical; Drug Storage; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Heterocyclic Compounds, 3-Ring - toxicity; Male; Medical sciences; Mice; Pharmacology. Drug treatments; Plasmodium berghei - drug effects; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0102396

A streamlined five-step chemical synthesis of rationally designed, simplified 3-aryltrioxane 8a is described. A noteworthy feature of this synthetic scheme is use of air rather than expensive molecular oxygen as the source of the pharmacologically critical peroxide unit in trioxane 8a. This simplified acetal trioxane carboxylic acid 8a is thermally stable, and it is hydrolytically stable in water even at 40 °C and pH 7.4 for at least 7 days. Preclinical evaluation of this water-soluble synthetic trioxane 8a in rodents shows it to have at least as good a therapeutic index (efficacy/toxicity) as that of water-soluble semisynthetic trioxane artelinic acid (5).