Synthesis and evaluation of phenylequine for antimalarial activity in vitro and in vivo Margaret A. L. Blackie a , Vanessa Yardley b , Kelly Chibale a,c, * a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa b Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK c Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa article info Article history: Received 8 September 2009 Revised 4 December 2009 Accepted 7 December 2009 Available online 11 December 2009 Keywords: Antiplasmodial Biological activity Bioorganic chemistry Chloroquine analogue Ferroquine abstract Synthesis of the potent antiplasmodial 4-aminoquinoline, phenylequine (PQ), is reported for the first time. PQ and the two analogues show increased efficacy in moving from the chloroquine sensitive D10 to the chloroquine resistant K1 strain in vitro. The in vivo efficacy of PQ, and salts thereof, have been determined in Plasmodium berghei ANKA and Plasmodium yoelii. Phenylequine hydrochloride has shown an ED 50 of 0.81 in P. yoelii (cf chloroquine ED 50 = 1.31). Ó 2009 Elsevier Ltd. All rights reserved. The search for new and effective antimalarial compounds con- tinues. The facts of the devastating effect of this disease are well documented. Over 40% of the world’s population is at risk of infec- tion and over 1 million fatalities result from plasmodial infections annually. 1 Of the four strains of Plasmodium which cause malaria in humans, Plasmodium falciparum remains the most problematic. As resistance to known drugs such as chloroquine (CQ) 1 increases, the need for effective alternatives grows. Over the last several dec- ades the modification of the side chain has proved to be a valuable trajectory of enquiry. 2 Ferroquine (FQ) 2, a ferrocene containing chloroquine analogue, 3 continues to show promise as a potential new chemotherapeutic agent, as it makes its way through the com- plex and demanding process of clinical trials. Ferroquine shows a significant absence of cross resistance with chloroquine. 4–6 We reasoned that a simple phenyl analogue of ferroquine, termed phenylequine (PQ) 3, might exhibit similar efficacy to FQ based on preliminary in vitro data (Fig. 1). 7 The phenyl analogue retains the necessary components for efficacy of a 4-aminoquinoline, that is, the 7-chloro group and weakly basic amino groups. 8 In a previ- ous study we have shown that ferroquine analogues lacking the 7- chloro group on the aminoquinoline moiety have shown in vitro efficacy significantly higher than would be expected. This efficacy suggests that the ferrocene moiety may have an additive and/or synergistic effect on antiplasmodial activity. 9 In this brief Letter we disclose the four-step synthesis of PQ 3 and two analogues 5 and 6, which were synthesised as a follow up to our earlier study to determine the role of the ferrocenyl moiety in ferroquine. 9 We have subsequently determined that a similar compound to 3 based on an acridine, 4, rather than a quinoline has previously been syn- thesised and evaluated for antiplasmodial activity over 50 years 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.12.030 * Corresponding author. E-mail address: Kelly.Chibale@uct.ac.za (K. Chibale). N HN Cl N N HN Cl N Fe N Cl HN OMe N N Cl HN N 1 2 3 4 N HN N 5 N Cl N H N H N 6 Figure 1. Structures of chloroquine (1), ferroquine (2), phenylequine (3), an acridine analogue of phenylequine (4), and two phenylequine analogues (5 and 6). Bioorganic & Medicinal Chemistry Letters 20 (2010) 1078–1080 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl