Targeting the Liver Stage of Malaria Parasites - American Chemical ...

Journal of Medicinal ChemistryTable 1. Structures of 8-Aminoquinolines with ActivityEqual or Superior to Primaquine in Monkeys 39Perspectivesignificant curative activity. 40 The quest to develop safer andmore active PQ analogues has been a mainstay in malariarelatedmedicinal chemistry. One such example is enamine CDRI80/53 or bulaquine (elubaquine), 38, which was approvedin India and is more active than PQ and is efficacious againstP. vivax and also significantly less toxic than the parentcompound. 41−44Other compounds with the PQ core include the imidazoquinesrecently described by Gomes and co-workers which haveshown interesting anti-LS activity in the micromolar range. 21 Forthis series, it appeared that the size of the substituent at R 2 wasessential for efficient inhibition (Table 2).Table 2. Structures of Imidazoquines and Activity against LSForms of P. berghei 21Tafenoquine, 47, formerly known as WR 238605, is a saferand more effective derivative of PQ that possibly inhibitscytochrome bc 1 in Plasmodium spp. 45−50 It displays a longerhalf-life, making it more suitable for long-term prophylaxis. Theefficacy and safety of tafenoquine treatment for radical cure ofP. vivax malaria are still under evaluation. Moreover, Strube andco-workers also showed the better tissue schizonticidal activityof 48 (NPC1161C) in infected primates compared to PQ, 51which was confirmed recently by Nanayakkara et al. with a100% cure rate at 1 mg/kg po for 3 days and no toxic effectsat 64 mg/kg in the same period of time. 52 It was also foundthat (−)-NPC1161B was several-fold more active than (+)-NPC1161A in murine models. The (−)-enantiomer was markedlyless toxic in mice than its (+)-counterpart and reducedhemotoxicity in a dog model of methemoglobinemia. 52 Thesuccess of tafenoquine prompted recent studies probing itsnearest chemical space. Jain and co-workers showed the curativeactivity of 2-tert-butyl analogue 49 in a dose of 25 mg kg −1 day −1po over 4 days in mice infected with P. berghei. Inthiscasebulkier substituents at C4, e.g., methyl and ethyl groups, weredetrimental for in vivo activity. 53 In another study by Lin and coworkers,the C5 biphenyl analogues, e.g., 50, did not presentsignificant causal prophylactic activity in infected mice. 54 Finally,our laboratory has disclosed recently PQ-artemisinin hybridswith promising results both in vitro and in vivo. Compound 52presented an IC 50 of 155 nM against hepatic Plasmodium bergheiin vitro. It also decreased parasite loads in the livers of infected998dx.doi.org/10.1021/jm201095h | J. Med. Chem. 2012, 55, 995−1012