The artemisinin antimalarials are activated via a Fenton-type reaction of an endoperoxide bond promoted by labile iron(II) in the parasite. The clinical value of these drugs and their novel chemical pharmacology has inspired the investigation of synthetic endoperoxides, including the clinical-stage 1,2,4-trioxolanes arterolane and artefenomel. These compounds share a common pharmacophore, with adamantane and cyclohexane rings flanking the 1,2,4-trioxolane moiety, and possessing a side chain at the 4' position of the cyclohexane. Hypothesizing that the disfavored chair conformer is the iron(II)-reactive one, we predicted that regioisomeric 3'-substituted analogs might exhibit useful properties, including enhanced stability to iron(II), distinct in vivo metabolism, and enhanced solubility due to their asymmetric structure. Here we report the first systematic study of 3'-substituted arterolane-like antimalarials, contrasting their in vitro and in vivo activities with the original 4' derivatives of Vennerstrom and co-workers. We synthesized arterolane and nine related 4' analogs previously reported to exhibit good in vivo efficacy in the P. berghei mouse malaria model. Synthesis of the desired 3' congeners was complicated by the fact that these compounds lack the internal symmetry of the 4' analogs and are chiral. We therefore devised a concise synthesis of the 3' derivatives that permitted full control of relative and absolute stereochemistry. In vitro testing revealed that the 3' variants exhibit low nanomolar activity against P. falciparum and the SAR trends were similar but not identical amongst the 4' comparators. We then performed extensive in vivo studies of the 3'-substituted analogs alongside their 4'-substituted comparators. While many analog pairs exhibited comparable efficacy in mice, selected analog pairs differed dramatically in this regard, consistent with our original hypothesis. A number of 3' analogs with in vivo properties superior to arterolane were identified. Overall our results suggest that a re-evaluation of the arterolane pharmacophore with a focus on 3' side chain substitution has the potential to yield new clinical candidates with improved properties.

In vivo structure-efficacy studies of regioisomeric arterolane-like endoperoxides

253rd National Meeting (2017)

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