Comprehensive metabolite identification study of arterolane using hydrophilic interaction liquid chromatography with quadrupole‐time‐of‐flight mass spectrometry

Abstract

In 2012, arterolane (ART) in combination with piperaquine received approval in India for the treatment of plasmodium-induced malaria; however, to date, a detailed metabolite identification study of ART has not been reported. Being polar in nature, ART shows early elution on reversed-phase columns which might be the rate-limiting factor of its systematic analytical studies. We have utilized hydrophilic interaction liquid chromatography (HILIC) to separate in vitro and in vivo metabolites of ART. Methods:The possible sites of metabolism were predicted by XenoSite software to obtain an initial assessment. In vitro studies were conducted by incubating the drug with liver microsomes such as human, rat and human S9 fractions. Later, in vivo studies were performed to check the metabolites in urine, faeces and plasma. The samples were pooled and subjected to the protein precipitation method before analysis by liquid chromatography/quadrupole-time-of-flight mass spectrometry (LC/QTOFMS). Results:We have observed 15 metabolites in this study which were phase I metabolites formed due to hydroxylation, dihydroxylation, peroxide bond scission and oxidation. Here, we report 11 metabolites of ART for the first time. The metabolic pathways and plausible structures were proposed according to accurate mass measurements and its MS/MS data. Conclusions:The present study comprehensively reports the in vitro and in vivo metabolism of ART mentioning 11 novel metabolites. Here, extensive use of HILIC has helped to efficiently separate various metabolites. These findings would help

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

“…Hydrolysis of the ester and subsequent formation of the benzotriazole activated ester 241 permitted differential synthesis of 165b (Scheme 8). 228,296‐298 …”