Randomized Dose-Ranging Controlled Trial of AQ-13, a Candidate Antimalarial, and Chloroquine in Healthy Volunteers

The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (C max ), were expressed as the fold of that particular effect with respect to their C max . The following tests were used at 37°C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (I Na and I Ks , respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemetherlumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and I Na and I Ks analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC 50 ) of halofantrine, which was lower than its C max , was confirmed. All the other compounds blocked hERG, with IC 50 s ranging from 3-to 30-fold their C max s. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its C max were confirmed and DHA blocked it at a concentration about 300-fold its C max . In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the I Na ion current and did so at about 30-fold its C max . No effect on I Ks was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents.

Section: Discussionmentioning

confidence: 99%

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Borsini

Crumb²,

Pace

et al. 2012

“…Quinoline derivatives such as MFQ and QUIN have strong activity against CQresistant strains of P. falciparum, and there have been several studies testing the activity of 4-aminoquinoline derivatives. In particular, among several 4-aminoquinoline derivatives, synthesized AQ-13, a three-carbon chain analog, exhibited activity against parasites resistant to CQ and MFQ (10) and was progressed to clinical trials (34). Recently, new classes of 4-aminoquinolines have been recognized and possess strong activity in vitro with excellent bioavailability (19,21,29,30,44).…”

mentioning

confidence: 99%

Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of Plasmodium In Vivo and In Vitro

Saénz

Mutka

Udenze

et al. 2012

New drugs to treat malaria must act rapidly and be highly potent against asexual blood stages, well tolerated, and affordable to residents of regions of endemicity. This was the case with chloroquine (CQ), a 4-aminoquinoline drug used for the prevention and treatment of malaria. However, since the 1960s, Plasmodium falciparum resistance to this drug has spread globally, and more recently, emerging resistance to CQ by Plasmodium vivax threatens the health of 70 to 320 million people annually. Despite the emergence of CQ resistance, synthetic quinoline derivatives remain validated leads for new drug discovery, especially if they are effective against CQ-resistant strains of malaria. In this study, we investigated the activities of two novel 4-aminoquinoline derivatives, TDR 58845, N 1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, and TDR 58846, N 1 -(7-chloro-quinolin-4-yl)-2,N 2 ,N 2 -trimethylpropane-1,2-diamine and found them to be active against P. falciparum in vitro and Plasmodium berghei in vivo. The P. falciparum clones and isolates tested were susceptible to TDR 58845 and TDR 58846 (50% inhibitory concentrations [IC 50 s] ranging from 5.52 to 89.8 nM), including the CQ-resistant reference clone W2 and two multidrug-resistant parasites recently isolated from Thailand and Cambodia. Moreover, these 4-aminoquinolines were active against early and late P. falciparum gametocyte stages and cured BALB/c mice infected with P. berghei. TDR 58845 and TDR 58846 at 40 mg/kg were sufficient to cure mice, and total doses of 480 mg/kg of body weight were well tolerated. Our findings suggest these novel 4-aminoquinolines should be considered for development as potent antimalarials that can be used in combination to treat multidrug-resistant P. falciparum and P. vivax.

“…This screen to identify novel antimalarial chemotypes targeting heme crystallization yielded compounds unlike those described in a notable previous effort, a radioisotope screen conducted at Roche, and unlike those based on modifying the quinoline scaffold (13,14,16,23). Possibly as a result of being able to conduct an HTS on unbiased libraries, the compounds identified in this screen had comparable antimalarial efficacies in both the CQ-sensitive strain 3D7 and the CQ-resistant strain Dd2 of P. falciparum.…”

Section: Discussionmentioning

confidence: 90%

Colorimetric High-Throughput Screen for Detection of Heme Crystallization Inhibitors

Rush

Baniecki

Mazitschek

et al. 2009

Malaria infects 500 million people annually, a number that is likely to rise as drug resistance to currently used antimalarials increases. During its intraerythrocytic stage, the causative parasite, Plasmodium falciparum, metabolizes hemoglobin and releases toxic heme, which is neutralized by a parasite-specific crystallization mechanism to form hemozoin. Evidence suggests that chloroquine, the most successful antimalarial agent in history, acts by disrupting the formation of hemozoin. Here we describe the development of a 384-well microtiter plate screen to detect small molecules that can also disrupt heme crystallization. This assay, which is based on a colorimetric assay developed by Ncokazi and Egan (K. K. Ncokazi and T. J. Egan, Anal. Biochem. 338:306-319, 2005), requires no parasites or parasite-derived reagents and no radioactive materials and is suitable for a high-throughput screening platform. The assay's reproducibility and large dynamic range are reflected by a Z factor of 0.74. A pilot screen of 16,000 small molecules belonging to diverse structural classes was conducted. The results of the target-based assay were compared with a whole-parasite viability assay of the same small molecules to identify small molecules active in both assays.