Mechanistic Evaluation of the Stability of Arylvinyl-1,2,4-trioxanes under Acidic Conditions for Their Oral Administration as an Antimalarial Drug.

A mechanistic approach to understand the course of metabolism for synthetic 1,2,4-trioxanes, potent antimalarial compounds, to evaluate their bioavailability for antimalarial action has been studied in the present work. It is an important parameter to study the course of metabolism of a drug candidate molecule when administered via oral route during its journey from oral intake to its target site. From the pharmacokinetics point of view, it determines the bioavailability of an active drug or a prodrug at the target point. In this work, synthetic arylvinyl-1,2,4-trioxanes 1a-u have been evaluated under various acidic conditions to mimic the milieu of the stomach (pH between 1.5 and 3.5) through which they have to pass when administered orally. The effect of acid on trioxanes led to their degradation into corresponding ketones and glyoxal. Under such acidic conditions glyoxal polymerized to form a nonisolable condensate product. The study indicates that the actual bioavailability of the drug is far less than the administered dose.