A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent

Abstract

Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ‐gold(I) hybrid molecule affects essential parasite targets, it inhibits β‐hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ‐gold(I) hybrid displayed an excellent in vitro antimalarial activity against the blood‐stage of Plasmodium falciparum and liver‐stage of Plasmodium berghei and efficacy in vivo against P. berghei, thereby demonstrating its multiple‐stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria.

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis

“…All reagents were used without prior purification. The THT-Au-Cl (THT: tetrahydrothiophene) and AuPQCl were synthesized as described in the literature [13]. All NMR experiments were recorded on a Bruker Avance III HD 500 spectrometer, 11.7 T at 298 K and using DMSO-d 6 as solvent.…”

“…1 H NMR ((CD 3 ) 2 SO) ppm 9.13 (sl, N2H); 8.39 (m, H2, H5, Hb); 8.07 (dd, J = 2 Hz, J =8 Hd); 7.87 (d, J = 2.5 Hz, H8); 7.56 (dd, J = 2 Hz, J = 9 Hz, H6); 7.42 (dd, J = 4 Hz, J = 8 Hz, Hc); 7.31 (d, J = 2.5 Hz, H3 ); 7.22 (dd, J = 2.5 Hz, J = 8.5 Hz, H5 ); 6.96 (d, J = 8.5 Hz, H6 ); 6.61 (d, J = 5.5 Hz, H3), 6.48 (d, J = 2.5 Hz, Hg); 6.29 (d, J = 2.5 Hz, He); 6.14 (d, 9 Hz, NbH); 4.09 (s, H7 ); 3.82 (s, Hl); 3.67 (m, Ha"); 2.95 (m, H8 ); 2.81 (m, Hd'); 1.60 (m, Hb', c'); 1.19 (m, H9 , a"). 13…”

“…The initial concept was that hybrid-based drugs could combine the antiplasmodial effects of its components (i.e., additivity or synergism) in a single molecule, facilitating the evaluation of pharmacokinetics, pharmaceutical formulation, and other aspects [7,8]. Among the concepts for designing hybrid-based drugs, there are three main possibilities: using non-cleavable chemical linkers [9,10], cleavable linkers (triggered by proteases or pH) [11,12] and transition metals that all play dual roles as cleavable chemical linkers and as antimalarials [13] (Figure 1). While all these possibilities have been investigated and have yielded promising results, the use of metals as chemical linkers offers the advantage of being pharmacologically active against parasites, while typically, organic chemical linkers are devoid of such effects.…”

“…A limitation of this therapeutic combination is that while there is a consistent summation of activity for the hepatic stages of the parasite [15,16], summation of activity for the asexual blood stages is variable and depends on the parasite strain and drug ratio [17,18]. To overcome this, we previously reported the synthesis of a hybrid of PQ and CQ linked by gold(I), denoted [AuCQPQ]PF 6 (1); this "three-in-one-molecule" was active against two stages of the Plasmodium life cycle and against three molecular targets of the parasite, confirming that it has multiple parasite stages and is a pleiotropic antimalarial agent [13]. However, hybrid (1) was not enough to overcome resistance to CQ when tested in vitro against CQ-resistant P. falciparum strains.…”

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine

“…Gold(I) was also used to tether two antimalarials, chloroquine and primaquine (PQ), into a single molecule. The resulting double drug exhibited higher activity against P. falciparum (3D7, W2) in vitro and P. berghei (liver-stage) in vivo than unlinked drugs [ 121 ].…”