Orally Active Antimalarial 3-Substituted Trioxanes:  New Synthetic Methodology and Biological Evaluation

• Published in: Journal of medicinal chemistry Vol. 41; no. 6; pp. 940 - 951
• Main Authors: Posner, Gary H, Cumming, Jared N, Woo, Soon-Hyung, Ploypradith, Poonsakdi, Xie, Suji, Shapiro, Theresa A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.03.1998; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - administration & dosage; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Chemistry, Medicinal; Drug Evaluation, Preclinical; Life Sciences & Biomedicine; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium falciparum - drug effects; Science & Technology; Structure-Activity Relationship; TRICYCLIC 1,2,4-TRIOXANES; AGENT ARTEMISININ; QINGHAOSU; MOLECULAR MECHANISM; MALARIA; DERIVATIVES; CHEMOTHERAPY; PEROXIDE; Antimalarial; Artemisinin; Oxygen heterocycle; Antiprotozoal agent; Peracetal; Plasmodium berghei; Structure activity relation; Parasiticid; Subcutaneous administration; Mechanism of action; Chemical synthesis; Protozoa; Apicomplexa; Rodentia; Benzene derivatives; Oral administration; Parasitosis; Tricyclic compound; In vitro; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Fluorine Organic compounds; Organic peroxide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970686e

On the basis of a mechanistic understanding of the mode of action of artemisinin-like antimalarials, a series of structurally simple 3-aryl-1,2,4-trioxanes 5 was designed and was prepared in three to five operations from commercial reactants. The 3-aryl group was attached in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro and in vivo antimalarial evaluations of these new trioxanes showed 12β-methoxy-3-aryltrioxanes 5g, 5j, 5k, and 5l to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially potent even when administered to rodents orally. As shown by rearrangement of hexamethyl Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3-aryltrioxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.