Schistosoma mansoni: antischistosomal activity of the four optical isomers and the two racemates of mefloquine on schistosomula and adult worms in vitro and in vivo.

Recent studies have shown that mefloquine (MQ) reveals interesting antischistosomal properties. We examined the antischistosomal activities of the erythro and threo isomers and racemates of MQ on newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro and in mice harbouring adult S. mansoni. The in vitro effects in the presence and absence of haemin were monitored by means of microcalorimetry, scanning electron microscopy and phenotypic evaluation. Incubation of NTS with the erythro derivatives at concentrations of 3 µg/ml and above resulted in convulsions, granularity, decrease in heat flow, and death while NTS incubated with the threo derivatives were only affected at high concentrations (100 µg/ml). Extensive tegumental alterations, decrease in metabolic activity, viability, and death were observed when adult schistosomes had been exposed to 10 µg/ml of the erythro compounds. Moderate tegumental and viability changes but reduced heat production rates were observed with the threo derivatives at 10 µg/ml. In the presence of haemin, all MQ derivatives showed pronounced antischistosomal properties against adult S. mansoni in vitro. In vivo, MQ derivatives achieved statistically significant total and female worm burden reductions ranging between 65.4% and 100%. The highest total worm burden reductions of 93.4% and 90.2% were observed following treatment with the erythro and threo racemates, respectively. In conclusion, the optical isomers and racemates of MQ show only moderate stereoselectivity, in particular in vivo. Our results may enhance our understanding of the mechanism of action and therapeutic profile of MQ derivates on schistosomes.

Mefloquine--an aminoalcohol with promising antischistosomal properties in mice.

BACKGROUND: The treatment and control of schistosomiasis, an often neglected tropical disease that exacerbates poverty, depends on a single drug, praziquantel. The large-scale use of praziquantel might select for drug-resistant parasites, hence there is a need to develop new antischistosomal compounds. Here, we report that the antimalarial drug mefloquine possesses promising antischistosomal properties in mice. METHODOLOGY/PRINCIPAL FINDINGS: A single dose of mefloquine (200 or 400 mg/kg) administered orally to mice infected with adult Schistosoma mansoni or adult S. japonicum resulted in high or complete total and female worm burden reductions (72.3%-100%). Importantly, high worm burden reductions were also observed for young developing stages of S. mansoni and S. japonicum harbored in the mouse. Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection. CONCLUSIONS/SIGNIFICANCE: Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality. Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes. It will be interesting to investigate whether mefloquine, which is widely and effectively used for the treatment of malaria, has an impact on schistosomiasis in areas where both malaria and schistosomiasis co-exist.

Utility of alkylaminoquinolinyl methanols as new antimalarial drugs.

Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the "opening" of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.

Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease.

During a program to investigate the biochemical basis of side effects associated with the antimalarial drug mefloquine, the authors made the unexpected discovery that the (-)-(R,S)-enantiomer of the drug is a potent adenosine A2A receptor antagonist. Although the compound was ineffective in in vivo animal models of central adenosine receptor function, it provided a unique nonxanthine adenosine A2A receptor antagonist lead structure and encouraged the initiation of a medicinal chemistry program to develop novel adenosine A2A antagonists for the management of Parkinson's disease (PD). The authors have synthesized and screened more than 2,000 chemically diverse and novel adenosine A(2A antagonists. Early examples from two distinct chemical series are the thieno[3,2-dy]pyrimidine VER-6623 and the purine compounds VER-6947 and VER-7835, which have high affinity at adenosine A2A receptors (K(i) values 1.4, 1.1, and 1.7 nmol/L, respectively) and act as competitive antagonists. In particular, VER-6947 and VER-7835 demonstrate potent in vivo activity reversing the locomotor deficit caused by the D2 receptor antagonist haloperidol, with minimum effective doses comparable with that of KW6002 (0.3 to 1 mg/kg). In conclusion, the authors have discovered potent, selective, and in vivo active nonxanthine adenosine A2A antagonists that have considerable promise as a new therapy for PD.

Discovery of novel targets of quinoline drugs in the human purine binding proteome.

The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear. In this study, we used a functional proteomics approach that exploited the structural similarities between the quinoline compounds and the purine ring of ATP to identify quinoline-binding proteins. Several quinoline drugs were screened by displacement affinity chromatography against the purine binding proteome captured with gamma-phosphate-linked ATP-Sepharose. Screening of the human red blood cell purine binding proteome identified two human proteins, aldehyde dehydrogenase 1 (ALDH1) and quinone reductase 2 (QR2). In contrast, no proteins were detected upon screening of the Plasmodium falciparum purine binding proteome with the quinolines. In a complementary approach, we passed cell lysates from mice, red blood cells, or P. falciparum over hydroxychloroquine- or primaquine-Sepharose. Consistent with the displacement affinity chromatography screen, ALDH and QR2 were the only proteins recovered from mice and human red blood cell lysate and no proteins were recovered from P. falciparum. Furthermore, the activity of QR2 was potently inhibited by several of the quinolines in vitro. Our results show that ALDH1 and QR2 are selective targets of the quinolines and may provide new insights into the mechanism of action of these drugs.

Use of artemisinin derivatives for the control of malaria.

Since 1994, the combination of mefloquine and artesunate is the standard treatment for uncomplicated Plasmodium falciparum malaria in the population of displaced persons on the Western border of Thailand. As a result, the fall of mefloquine efficacy was stopped and the incidence of falciparum malaria reduced. This is attributed to the effects of the artemisinin derivatives on transmissibility. Similar trends were observed in Vietnam where artemisinin is widely used. Combination therapies that include an artemisinin derivative could have a major role in the control of malaria and the spread of drug resistance.

In vitro and clinical correlates of mefloquine resistance of Plasmodium falciparum in eastern Thailand.

A series of isolates of Plasmodium falciparum from eastern Thailand was collected prior to and after treatment failure with mefloquine. Patterns of drug sensitivity to standard and new antimalarials were characterized by using an in vitro assay based on the inhibition of schizont maturation. In vitro levels of mefloquine sensitivity of isolates were correlated with clinical treatment failures. In vitro parasite resistance to mefloquine is defined as an inhibitory dose-50 value greater than 20 nM. For isolates collected prior to treatment, there was no significant difference in mefloquine sensitivity patterns between subsequent successes and failures, suggesting that mefloquine treatment failures could not be predicted based on in vitro sensitivity of pretreatment isolates. A series of paired isolates were collected both prior to treatment with mefloquine and after recrudescence. Recrudescent isolates showed significant decreases in sensitivity to mefloquine, WR 194965, enpiroline, and halofantrine; no significant changes in sensitivity to amodiaquine, qinghaosu, and pyrimethamine; and an increase in sensitivity to chloroquine.