Extraordinarily Potent Antimalarial Compounds: New, Structurally Simple, Easily Synthesized, Tricyclic 1,2,4-Trioxanes

Gary H. Posner, Chang Ho Oh, Lucia Gerena, Wilbur K. Milhous

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99 Scopus citations

Abstract

New, racemic, tricyclic trioxane alcohol 3 was designed and synthesized as a structurally simple analog of clinically useful, tetracyclic, antimalarial artemisinin. A series of 20 ester and ether derivatives of alcohol 3 were prepared easily, without destruction of the essential trioxane system. Chemical structure-antimalarial activity for each derivative was evaluated in vitro against chloroquine-resistant and chloroquine-sensitive Plasmodium falciparum parasites. Many of these derivatives were highly efficacious; carboxylate ester 9f, carbamate ester 10a, and sulfonate ester 12a had antimalarial potency similar to that of artemisinin, and carboxylate esters 9b and 9d, carbamate esters 10b and 10c, and phosphate esters 11a-c had antimalarial potency up to 7 times higher than that of artemisinin. Several of these most active analogs (e.g., carboxylate 9b and carbamates 10a and 10c) are stable crystalline solids, a feature of considerable practical value for any new drug candidate.

Original languageEnglish
Pages (from-to)2459-2467
Number of pages9
JournalJournal of Medicinal Chemistry
Volume35
Issue number13
DOIs
StatePublished - 1992 Jun 1
Externally publishedYes

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