Dual-acting diamine antiplasmodial and chloroquine resistance modulating agents Susan Yeh a , Peter J. Smith a , Kelly Chibale b, * a Division of Pharmacology, Department of Medicine, University of Cape Town Medical School, Observatory 7925, South Africa b Department of Chemistry and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa 1. Introduction The global picture of malaria is such that 300–500 million people are infected and at least one million die each year, mostly children under the age of 5 [1]. Chloroquine (CQ) has been the most important antimalarial drug for almost half a century. Although this well-tolerated quinoline-based drug appears to have failed as a first-line antimalarial in most parts of the world, it may be resurrected by combination therapy with effective resistance reversal agents [2]. CQ resistance was very slow to develop, suggesting multiple mutations were required to produce the resistance phenotype. Laboratory gene mapping efforts have been carried out by investigators worldwide and a CQ resistance candidate gene was eventually identified on chromosome 7 and thought to be responsible for the difference in CQ accumulation between CQ-sensitive and -resistant isolates [3–5]. Knowledge about CQ resistance and CQ’s mode of action has been a subject of debate over the years. A milestone in CQ resistance was established by the discovery of the lysosomal integral protein, PfCRT (Plasmodium falcparum CQ resistance transporter) in genetic cross analysis in vitro [6], and its absolute association with CQ resistance. Work in multi-drug resistance (MDR) in cancer has shown the possibility to restore an anticancer agent’s efficacy by using a combination of chemosensitizers at safe therapeutic biochemical pharmacology 72 (2006) 156–165 article info Article history: Received 1 March 2006 Accepted 12 April 2006 Keywords: Malaria Antimalarial agents Chloroquine Drug resistance Privileged structures Chemosensitizers abstract On the basis of structural features known to be critical for the antimalarial activity, accumulation and uptake of chloroquine (CQ), as well as chemosensitization of CQ resistant Plasmodium falciparum, an exploratory novel series of potential dual acting antiplasmodial and chemosensitizing agents was designed and synthesized for biological evaluation. All four compounds contain a common alkyl side chain with two amino groups and differ only in the chemical nature of the hydrophobic aromatic moieties. Among them, N 0 -[4- (biphenyl-2-ylmethoxy)-benzyl]-N,N-dimethyl-propane-1,3-diamine (P7) displayed the greatest potential as a dual-acting antiplasmodial agent against CQ-resistant strains ðIC K1=RSA11 50 < 0:6 mMÞ and chemosensitizer (RMI K1 = 0.67; RMI RSA11 = 0.82) while displaying low in vitro cytotoxicity against a mammalian cell line (CHO). At 1 mM, P7 caused a 8.5 and 4-fold potentiation in CQ accumulation in resistant P. falciparum K1 and RSA11 strains, respectively. In a parallel experiment, 1 mM verapamil showed a 6.5 (K1) and 2 (RSA11)-fold increase in CQ accumulation. The preliminary studies point to structural features that may determine antiplasmodial and/or CQ resistance modulating activity in this new series of compounds. An additive effect was observed against both CQ S (D10) and CQ R (RSA11) strains when CQ and P7 were used at their corresponding IC 50 concentrations in isobologram analysis. # 2006 Elsevier Inc. All rights reserved. * Corresponding author. Tel.: +27 21 650 2553; fax: +27 21 689 7499. E-mail address: chibale@science.uct.ac.za (K. Chibale). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/biochempharm 0006-2952/$ – see front matter # 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2006.04.006