Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.
There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc 1 . Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.T he discovery of atovaquone 20 years ago validated the malaria parasite's mitochondrial electron transport chain (ETC) as an exploitable drug target. Atovaquone targets the ETC at the level of the bc 1 complex (1), with inhibition preventing proton pumping, resulting in a loss of mitochondrial membrane potential (2) and eventual organelle dysfunction, an important function of which is to provide intermediates for pyrimidine synthesis (3, 4). The bc 1 complex requires reducing equivalents provided by ubiquinol, which in turn is generated by membrane-bound dehydrogenases upstream in the ETC that catalyze redox reactions by reducing ubiquinone. The parasite lacks the canonical protonmotive NADH dehydrogenase (Complex I) but instead harbors a bacterial-like type II NADH:ubiquinone oxidoreductase, Plasmodium falciparum NDH2 (PfNDH2) (5). Based on these key observations, we undertook a drug-discovery initiative to develop costeffective inhibitors capable of inhibiting PfNDH2 with the goal of providing antimalarials that overcome the limitations of the expensive atovaquone. Although our initial drug-discovery efforts were focused on optimization of activity versus PfNDH2, we found, during hit-to-lead development, that optimized structures with single-digit nanomolar activity versus the primary target ...
A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure–activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc1, and studies to determine the potential advantage of this dual-targeting effect are in progress.
T he ability to probe the base of a wound to periosteum or bone (the "probe-to-bone" test) is increasingly used to indicate the likelihood of underlying osteomyelitis. The original study (1) reported sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values of 66, 85, 89, and 56%, respectively. However, this work has been criticized on the grounds of the high pretest probability of the disease (2), since the prevalence of osteomyelitis in the chosen sample (in-patients with clinically overt infection) was 66%. It follows that the usefulness of the test may be very different in less-selected populations. We have therefore determined the validity of the probe-to-bone test in a consecutive series of outpatients attending our own multidisciplinary service.A total of 81 patients (with a total 104 foot ulcers) attended the clinic over a 5-week period in May-June 2005. Ulcers were probed by one of two specialist podiatrists following debridement. The diagnosis of osteomyelitis was determined by one of two expert diabetologists, who were blind to the results of the probe to bone test. The diagnosis of osteomyelitis was based in each case on the presence of clinical signs of infection (inflammation with or without serous or purulent discharge) in association with radiologic evidence of bone destruction with interruption of the cortex (either at presentation or at any stage over the ensuing 8 weeks), supported when necessary by magnetic resonance imaging and microbiologic analysis of deep tissue samples. Those who were diagnosed with osteomyelitis included those in whom the diagnosis had already been made at the time of probing and those in whom the diagnosis was made later. Nineteen (23.5%) patients were diagnosed with osteomyelitis complicating foot ulcers, in two of whom bone infection complicated two separate nonadjacent ulcers. Three patients had two or more nonadjacent ulcers, of which only one was associated with osteomyelitis. A total of 14 patients had osteomyelitis complicating a single ulcer. A total of 21 ulcers (20.2% of 104) were associated with osteomyelitis. The probe-to-bone test was positive in 8 of these 21 ulcers and in 7 of 83 without associated bone infection (sensitivity 38%, specificity 91%). While the NPV was 85%, the PPV (the probability that a patient with a positive test would have osteomyelitis) was only 53%. It is possible that the calculation of both sensitivity and NPV might be in part explained by the fact that some cases of osteomyelitis may already have been responding to treatment at the time of probing, but this would not have affected the calculation of either the specificity or the PPV.These data emphasize that the predictive value of a positive probe-to bone test in the original report was influenced by the high prevalence of osteomyelitis in the population studied. The prevalence of osteomyelitis in the present population was still high at 23.5% patients (20.2% ulcers) but was only approximately one-third of that in the earlier study, and the PPV was corresp...
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