Article pubs.acs.org/jmc
Cite This: J. Med. Chem. 2018, 61, 3422−3435
Synthesis and Structure−Activity Relationships of the Novel Antimalarials 5‑Pyridinyl-4(1H)‑Pyridones José M. Bueno,*,†,§ Félix Calderon,† Jesús Chicharro,† Juan C. De la Rosa,† Beatriz Díaz,† Jorge Fernández,† José M. Fiandor,† María T. Fraile,† Mercedes García,† Esperanza Herreros,† Adolfo García-Pérez,† Milagros Lorenzo,† Araceli Mallo,† Margarita Puente,† Anas Saadeddin,† Santiago Ferrer,† Iñigo Angulo-Barturen,†,⊥ Jeremy N. Burrows,‡ and María L. León*,† †
Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Calle de Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain ‡ Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva, Switzerland S Supporting Information *
ABSTRACT: Malaria is still one of the most prevalent parasitic infections in the world, with half of the world’s population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant Plasmodium strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4(1H)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4(1H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains.
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INTRODUCTION Malaria continues to be a leading cause of death on the planet, with 50% of the population being exposed to the risk of infection. More than 200 million new clinical cases are estimated annually, leading to approximately 800 000 deaths each year, primarily of children under five and expectant mothers.1 Although the control of the disease still depends on chemotherapy, the spread of Plasmodium falciparum strains resistant to most of the antimalarials currently in use, including chloroquine;2 the limited number of drugs currently available against malaria;3 and the alarming evidence pointing to the appearance of P. falciparum strains resistant or less sensitive to artemisinin derivatives,4 the basic components of the current gold-standard combinations for the treatment of malaria (artemisinin-combination therapies, ACTs), has fueled the research effort to find novel drugs for the treatment of malaria.5,6 The mitochondrial respiratory chain of P. falciparum is an attractive target for chemotherapy, because it is different from the analogous mammalian system,7−10 and it is essential for the parasite. In the erythrocytic stages, the mitochondria are involved in several essential metabolic processes, which interestingly do not include ATP production and vary depending on the species of parasite. Therefore, proteins involved in mitochondrial physiology have the potential for antiparasitic-drug discovery.8 © 2018 American Chemical Society
The election of the mitochondrial electron-transport chain of P. falciparum as a putative target in antimalarial-drug discovery was validated in the successful development of atovaquone (Figure 1), introduced into therapy in 1997 in combination with proguanil. The combination atovaquone−proguanil is currently used in treating multidrug-resistant malaria and for prophylaxis in areas with chloroquine resistance.11 Atovaquone inhibits the P. falciparum mitochondrial respiratory chain at the cytochrome bc1 level (complex III), demonstrating that cytochrome bc1 can be a drug target in the prevention and treatment of malaria. The bc1 complex is central to mitochondrial function in P. falciparum, and it is composed of two binding sites, Qo and Qi, for the oxidation of ubiquinol and the reduction of ubiquinone, respectively. Most of the antimicrobial drugs, such as atovaquone, target the Qo site.12 Unfortunately, the rapid rise of atovaquone resistance, mainly caused by mutations at the Qo binding site, has compromised the use of atovaquone as a firstline antimalarial. In our efforts to find novel antimalarials, scientists at GSK have developed a medicinal-chemistry program based on the 4(1H)-pyridone core present in the known anticoccidial drug clopidol (Figure 1). Although initially it was presumed that Received: October 9, 2017 Published: March 28, 2018 3422
DOI: 10.1021/acs.jmedchem.7b01256 J. Med. Chem. 2018, 61, 3422−3435
Journal of Medicinal Chemistry
Article
Figure 1. Structures of atovaquone, clopidol, the previous pyridone hits, and the new polar derivatives.
CH2OH groups exerted different effects on the antimalarial activities depending on their positions.21 As shown in Figure 1, although the hydroxymethyl group induces a significant drop in antimalarial activity in vitro in comparison with its nonhydroxylated analogue when it is located at position C2, it is possible to maintain high levels of activity by attaching the hydroxymethyl group at position C6 of the 4-pyridone ring, thus leading to potent and more polar compounds with improved pharmacokinetic (PK) properties. Within the strategies aimed at improving the physicochemical properties and oral bioavailabilities, in addition to the introduction of CH2OH groups at position C6, we have also explored the effect of replacing the phenyl rings on the lipophilic side tail with more polar heterocycles. In this paper, we report the synthesis and biological evaluation of a new series of antimalarial 4(1H)-pyridone derivatives bearing pyridine rings substituted at position C5 (Figure 2). As shown, we have
4(1H)-pyridones were binding to the Qo site in cytochrome bc1,13 recent studies seem to point to Qi as the binding site for these compounds.14 Clopidol displayed weak antimalarial activity in animal models,15 and there is evidence indicating that its anticoccidial action is related to mitochondrial impairment.16 The strategy for increasing the antimalarial activity of clopidol was the replacement of one of the chlorine atoms with different lipophilic side chains. As a result, a series of potent 2,6dimethyl-4(1H)-pyridones, such as GW844520 and GW308678, bearing diphenyl-ether moieties, have been prepared (Figure 1). The novel compounds have been shown to be superior to chloroquine in vitro against erythrocytic stages of the parasite and in vivo in the P. yoelii mouse model.17 Compared with clopidol, the most active 4(1H)-pyridones prepared showed >500-fold improvements in their in vitro activities (IC50 for inhibition of P. falciparum) and ca. 100-fold improvements in their in vivo efficacies (ED50 in a murine model of P. yoelii). In general, the most potent compounds were characterized as class II compounds according to the Developability Classification System,18 with high permeabilities and low solubilities in aqueous media. They display high oral bioavailabilities in mice and rats at low doses administered as solution formulations (50−100% at doses
