Optimization of 1,2,3,4-Tetrahydroacridin-9(10<i>H</i>)-ones as Antimalarials Utilizing Structure–Activity and Structure–Property Relationships

Cross, R. Matthew; Maignan, J.; Mutka, Tina; Luong, Lisa; Sargent, Justin; Kyle, Dennis E.; Manetsch, Roman

doi:10.1021/jm200015a

Cited by 51 publications

(64 citation statements)

References 40 publications

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“…Plates were incubated at 37°C for 3 h and then washed three times with PBS. Serial dilutions of experimental compounds were prepared as previously described (35), added to parasite-infected HepG2 cells in triplicate, and incubated at 37°C for 44 h. Following the incubation, cells were washed once with PBS and then lysed with 10 l of cell culture lysis reagent (Promega Luciferase Assay system kit; Promega, Madison, WI). Immediately after cell lysis, 100 l of Luciferase Assay substrate was added, and then the parasite lysates were analyzed.…”

Section: Methodsmentioning

confidence: 99%

4(1H)-Quinolones with Liver Stage Activity against Plasmodium berghei

LaCrue

Saénz

Cross

et al. 2013

Antimicrob Agents Chemother

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bWith the exception of primaquine, tafenoquine, and atovaquone, there are very few antimalarials that target liver stage parasites. In this study, a transgenic Plasmodium berghei parasite (1052Cl1; PbGFP-Luc con ) that expresses luciferase was used to assess the anti-liver stage parasite activity of ICI 56,780, a 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), as well as two 3-phenyl-4(1H)-quinolones (P4Q), P4Q-146 and P4Q-158, by using bioluminescent imaging (BLI). Results showed that all of the compounds were active against liver stage parasites; however, ICI 56,780 and P4Q-158 were the most active, with low nanomolar activity in vitro and causal prophylactic activity in vivo. This potent activity makes these compounds ideal candidates for advancement as novel antimalarials. Malaria kills more than one million people throughout the world annually, and with the increase in drug-resistant parasites, insecticide-resistant vectors, and the lack of a vaccine, new drugs are needed to treat this devastating disease (1). Infection in the mammalian host is initiated when a female Anopheles mosquito ingests a blood meal and injects sporozoites into the vertebrate host. The sporozoites migrate to the liver, invade hepatocytes, and undergo further development resulting in the release of merozoites into the bloodstream (2, 3). In the case of Plasmodium vivax, sporozoites form hypnozoites that can lie dormant in the liver for months or years before causing a relapse (4). The mechanism responsible for the formation and subsequent activation of hypnozoites is not clearly understood. Some suggest that the extended duration of infection may be evolutionarily advantageous, allowing for enhanced opportunities to transmit to new hosts (5). Relapses caused by hypnozoites of P. vivax make this species difficult to eradicate (5).Currently, primaquine and atovaquone are the only commercially available antimalarials that target liver stage parasites. Primaquine and tafenoquine, both 8-aminoquinolines, are the only drugs shown to kill hypnozoites (6-8). However, due to the short half-life of primaquine in plasma, a lengthy treatment regimen of 14 days is required, which can make patient compliance difficult. Additionally, widespread use in areas of endemicity is limited because individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are unable to take primaquine due to a high risk of severe hemolytic anemia (9, 10). Therefore, it has become necessary to develop novel compounds that target the liver stages of parasite development and are safe for use in individuals from regions of endemicity (8).Endochin, a 4(1H)-quinolone compound, was identified in the 1940s as a potential antimalarial. Salzer et al. (11) found that endochin had liver and blood stage activity in avian malaria models; however, due to the lack of appropriate preclinical models, additional studies were not conducted (11). The compounds related to endochin also have activity against Plasmodium cynomolgi liver stages (12), and more recently, studies have shown these...

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Section: Methodsmentioning

confidence: 99%

4(1H)-Quinolones with Liver Stage Activity against Plasmodium berghei

LaCrue

Saénz

Cross

et al. 2013

Antimicrob Agents Chemother

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“…Many recent compound series based on 4-(1H)-quinolone/4-pyridone scaffolds are also proposed to bind to the Qi site [44]. This motif appears to be a privileaged scaffold for the inhibition of cytochrome bc1 in both Plasmodium and Toxoplasma [44][45][46][47][48]. There are a number of advantages to targeting the Qi site: (i) targeting a novel site within a validated target increases confidence that inhibition of this target will have the desired phenotypic response; (ii) there are no existing resistance mechanisms.…”

Section: Cytochrome Bc1 (Complex Iii)mentioning

confidence: 99%

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

Gordon¹,

Fishwick²,

McPhillie

2016

CTMC

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Abstract:Since the recent renaissance of phenotypic screening in the field of protozoan drug discovery, is there still an opportunity for the structure-based design of new anti-protozoan agents? Target-based approaches should be used in parallel to phenotypic screening to strengthen the pipeline of anti-protozoan agents. We give an overview of the protozoan drug discovery landscape highlighting four protein targets of interest: cytochrome bc1, dihydroorotate dehydrogenase, dihydrofolate reductase and calcium-dependent protein kinase 1. We discuss recent structure-based design efforts to inhibit these targets, reviewing their crystal structures and their ability to accommodate potent and selective compounds. Finally, we discuss future opportunities to apply structure-based methods to promising molecular targets within protozoan parasites discovered using chemical genomics.

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“…There are several antimalarials in the drug development pipeline that target pyrimidine biosynthesis (23,26), and ones that target the respiratory chain (17,(27)(28)(29)(30)(31)(32). Some of the new cytochrome bc 1 inhibitors are effective against atovaquone-resistant parasites (33), but it would be of interest to determine if they also participate in the cross talk described here.…”

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confidence: 99%

Atovaquone Tolerance in Plasmodium falciparum Parasites Selected for High-Level Resistance to a Dihydroorotate Dehydrogenase Inhibitor

Guler

White

Phillips

et al. 2015

Antimicrob Agents Chemother

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Atovaquone is a component of Malarone, a widely prescribed antimalarial combination, that targets malaria respiration. Here we show that parasites with high-level resistance to an inhibitor of dihydroorotate dehydrogenase demonstrate unexpected atovaquone tolerance. Fortunately, the tolerance is diminished with proguanil, the second partner in Malarone. It is important to understand such "genetic cross talk" between respiration and pyrimidine biosynthesis since many antimalarial drug development programs target these two seemingly independent pathways. Malarone is an antimalarial drug combination, often prescribed for travelers as a prophylactic. but its high cost so far has limited its general use in countries where malaria is endemic. The patent for this drug expired in 2013, and its global usage could soon surge. Atovaquone and proguanil are the synergistic pair of antimalarials that make up this effective, well-tolerated cocktail. While the mechanism of action for proguanil remains uncertain (1, 2), it is well know that atovaquone targets the cytochrome bc 1 complex of the Plasmodium falciparum respiratory chain (3, 4). One function of this mitochondrial pathway is to generate a proton gradient that is required for maintaining the membrane potential for important processes such as protein synthesis, heme biogenesis, and the citric acid cycle (reviewed in reference 2). Importantly, the P. falciparum cytochrome bc 1 complex has been implicated in the direct regeneration of oxidized ubiquinone for dihydroorotate dehydrogenase (DHODH), a key enzyme in the biosynthesis of pyrimidine nucleotides (5-7). Thus, DHODH is physically and functionally tied to the respiratory chain.Recently, P. falciparum parasites resistant to DSM1, a potent inhibitor of DHODH (8, 9), were generated at two levels (333 nM for round 1 and 3 or 10 M for round 2) (10). Amplification of the genome segments that encompassed the DHODH gene were responsible for the observed phenotype. Whole-genome sequence methods ruled out resistance-conferring mutations elsewhere, and no alterations in the sensitivities to several unrelated antimalarials were detected. However, here we report the unexpected development of tolerance to atovaquone in parasites resistant to higher levels of the DHODH inhibitor DSM1 (round 2).Following DSM1 selection and subcloning (10), atovaquone sensitivity was tested. Round 1 parasites (ϳ3-fold DSM1 resistance) exhibited wild-type sensitivity to atovaquone in a 72-h assay (Fig. 1A and Table 1). Long-term exposure to low levels of atovaquone confirmed the sensitivity of these parasites: 10 nM atovaquone completely prevented the proliferation of parental Dd2, as well as round 1 parasites within 2 days, and continued to do so over an extended period of 8 days (Fig. 1C and D, red lines). We further assessed the survival of Dd2 and round 1 clone C by exposing small clonal populations of parasites to atovaquone before extensive washing and replating in the absence of drug and following the number of viable colonies over 60 days (11)...

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Optimization of 1,2,3,4-Tetrahydroacridin-9(10H)-ones as Antimalarials Utilizing Structure–Activity and Structure–Property Relationships

Cited by 51 publications

References 40 publications

4(1H)-Quinolones with Liver Stage Activity against Plasmodium berghei

4(1H)-Quinolones with Liver Stage Activity against Plasmodium berghei

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

Atovaquone Tolerance in Plasmodium falciparum Parasites Selected for High-Level Resistance to a Dihydroorotate Dehydrogenase Inhibitor

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