3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum

Abstract

Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum. Malaria is a devastating infectious disease worldwide, with 135 million to 287 million cases in 2014 and an estimated 627,000 deaths annually (1). The use of chloroquine (CQ), a once highly effective and inexpensive antimalarial drug, has been discontinued due to the rise and spread of CQ resistance in most regions of endemicity (2). Chloroquine has been shown to accumulate in the digestive vacuole (DV), whereby it binds to hemin and interferes with hemozoin crystal formation (3). Chloroquineresistant parasites have been shown to encode a mutant form of the Plasmodium falciparum chloroquine resistance transporter (PfCRT) (4). However, several novel drug candidates based on CQ structure, with modifications of both the side chain and the quinoline ring, have been shown to bypass PfCRT-mediated resistance (5-8). In this report, we evaluated the antimalarial activities of three novel halo chloroquine derivatives, with halogen groups (iodine, bromine, or chlorine) at the 3rd position of 4-aminoquinoline. The 3-halo derivatives of chloroquine were isolated as diphosphate or triphosphate white solids and characterized by elemental analysis, nuclear magnetic resonance (NMR), and infrared (IR) spectroscopy (detailed elsewhere). The antimalarial activity of the three halo derivatives against CQ-susceptible (3D7) and -resistant (Dd2) strains of P. falciparum was evaluated in vitro. Figure 1 shows the proliferation of the 3D7 and Dd2 strains of P. falciparum in the presence of increasing molar concentrations of CQ or 3-halo-CQ derivatives. The three derivatives inhibited the proliferation of 3D7 and Dd2 P. falciparum to different extents, with 50% inhibitory concentrations (IC 50 s) of 367 to 747 nM against 3D7 and 623 nM to 1,163 nM against Dd2. These IC 50 s were higher than those seen with CQ for the two different strains (e.g., 21 nM and 178 nM for 3D7 and Dd2, respectively). However, unlike CQ, the 3-halo-CQ derivatives were equally effective against CQ-susceptible and -resistant parasites, with ϳ2-fold differences in IC 50 s versus an ϳ8.5-fold difference for CQ. These results suggest that, unlike CQ, the resistance mechanisms in Dd2 are less effective against the 3-halo derivatives (Fig. 1). Hence, modification of the 3rd position on the 4-aminoquinoline has the potential to bypass Dd2 resistance mechanisms (e.g., mutations in PfCRT and PfMDR1) but reduces the 3-halo-CQ antiproliferative activity against the parasite. However, it is presently unc...

Synthesis and Photolysis Properties of a New Chloroquine Photoaffinity Probe

“…We synthesized a chloroquine photoaffinity labelled analog with minimal modification of the quinoline structure. The aryl azide was placed at the 3-position, a position that our group has previously taken advantage of [ 5 , 6 ]. The strategy for this preparation is to use an Ullman coupling for the formation of a C sp2 —heteroatom bond at the 3-position [ 7 ].…”

“…1 H NMR (500 MHz, chloroform-d) δ 2.52 (q, J = 7.2 Hz, 4H), 2.40 (d, J = 6.5 Hz, 5H), 1.51-1.42 (m, 3H), 1. 34 N4-(7-chloroquinolin-4-yl)-N1,N1-diethyl-N4-methylpentane-1,4-diamine (6) The mixture of 4,7-dichloroquinoline (500 mg, 2.5 mmol) and N 1 ,N 1 -diethyl-N 4methylpentane-1,4-diamine (652.6 mg, 3.8 mmol, 1.5 equiv.) were placed in a microwave flask with p-toluenesulfonic acid (816 mg, 4.3 mmol, 1.7 equiv.).…”

Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19

“…It has been found that a variety of compounds without fixed chemical properties can restore the sensitivity to CQ ( de Souza et al, 2019 ). These compounds, when co-administrated with CQ, were observed to increase the sensitivity of some CQ resistant P. falciparum strains in vitro ( Ch'ng et al, 2013 ; Deane, Summers, Lehane, Martin, & Barrow, 2014 ; Edaye, Tazoo, Bohle, & Georges, 2015 ; Kashyap et al, 2018 ). The major mechanism involved is the inhibition of the active drug efflux pump pfcrt ( van Schalkwyk & Egan, 2006 ).…”

Chloroquine Urea Derivatives: Synthesis and Antitumor Activity in Vitro

“…Numerous chloroquine derivatives have been prepared in order to overcome Plasmodium resistance, the main problem in malaria treatment (see, for example, refs. [14][15][16] or in finding new anticancer agents (refs. 17-20).…”