The Use of Sn-10,275 in the Prophylaxis and Treatment of Sporozoite-Induced Viv Ax Malaria (Chesson Strain) 1

H uman schistosomiasis is a neglected tropical disease whose burden is mainly concentrated in sub-Saharan Africa and affects approximately 207 million people (30). The three main schistosome species parasitizing humans are Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum. Today, treatment with praziquantel is the core component of schistosomiasis control programs (32,34,35). There is no question that heavy reliance on a single drug bears a risk of drug resistance development. Indeed, in different regions of endemicity, lower cure rates have already been observed (9). An additional disadvantage of praziquantel is its stage-dependent susceptibility, showing only poor efficacy against immature schistosome stages (23). Therefore, drug discovery in the field of schistosomiasis remains an important task. Antischistosomal properties of the antimalarial drug mefloquine were first mentioned in 2008, when it was shown that a dosage of 150 mg/kg of body weight significantly reduced the egg burden in S. mansoni-infected mice (33). Further investigations revealed that mefloquine possesses good in vivo efficacy, with a single oral dosage of 200 mg/kg resulting in a total worm burden reduction of 72.3% in S. mansoni-infected mice. Another interesting characteristic of mefloquine is its efficacy against the juvenile immature stage (13). Finally, a randomized clinical trial that investigated the effect of mefloquine and mefloquine-artesunate in S. haematobium-infected patients was recently performed. It was shown that a combination therapy of mefloquine-artesunate resulted in moderate cure and high egg reduction rates (15).Based on these promising findings, we were motivated to test mefloquine-related compounds belonging to the three major groups of arylmethanols well described in antimalarial research, namely, 4-quinolinemethanols, 9-phenanthrenmethanols, and 4-pyridinemethanols (4), in order to elucidate their potential as antischistosomal lead candidates. In addition, a study on mefloquine-related compounds might provide us with a deeper understanding of structural features needed for antischistosomal activity of arylmethanols. The selected nine arylmethanols were first tested against S. mansoni schistosomula and adults in vitro. Promising compounds were followed up in vivo. Candidates characterized by high in vivo activity against S. mansoni were tested against S. haematobium. In addition, promising candidates were incubated in the presence of hemoglobin, hemin, or red blood cells to compare drug activities in relation to the postulated mechanistic heme dependency of arylmethanols (6). Finally, isothermal microcalorimetry (IMC) was used to investigate the antischistosomal properties of lead candidates in greater detail and to compare their levels of activity with mefloquine.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Antischistosomal Activities of Mefloquine-Related Arylmethanols

Ingram

Ellis

Keiser

2012

“…Unlike the latter compound classes, which were studied in-depth experimentally and clinically in this earlier program (2,3,5,6,8,16,19), the 4-pyridinemethanols received very little attention at the chemical synthesis and screening levels. Only three derivatives were prepared and examined for activity against a random group of avian malarias.…”

Section: Discussionmentioning

confidence: 99%

Antimalarial Activities of Various 4-Pyridinemethanols with Special Attention to WR-172,435 and WR-180,409

Schmidt

Crosby

Rasco

et al. 1978

Pilot appraisals of the activities of 10 specially selected 2,6-substituted-4-pyridinemethanols against acute Plasmodium falciparum infections in owl monkeys identified three derivatives that were two to three times as active as chloroquine against infections with a 4-aminoquinoline-susceptible strain and, at the same doses, were equally effective against infections with a strain fully resistant to treatment with maximally tolerated doses of chloroquine, quinine, and pyrimethamine. Two of these derivatives, 409, deemed worthy of evaluation in human volunteers, were studied in greater depth in owl monkeys infected with either the multidrug-resistant Smith strain of P. falciparum or the pyrimethamine-resistant Palo Alto strain of P. vivax. These studies showed (i) that at the same total oral dose, 3-day and 7-day treatment schedules were equally effective and slightly superior to a single-dose schedule; (ii) 98,057, a direct descendent of one of the three 4-pyridinemethanols examined in the World War II Malaria Chemotherapy Program (30) and the first of the newly synthesized derivatives to effect cure of P. berghei infections, and nine of the most promising derivatives developed subsequently (see Table 1 for identification and structures) were submitted to our laboratory for pilot appraisals of activities against infections with chloroquine-resistant and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Three of the 10, 435,117,409, exhibited outstanding activity. These compounds were essentially equal to one another in activity in this human plasmodium model. They effected cure of infections with chloroquine-resistant strains at approximately one-third the dose of chloroquine required to cure infections with strains susceptible to this 4-aminoquinoline, and their effectiveness was not compromised by concomitant resistance to pyrimethamine.The

“…Although these comparisons involved work with small numbers of volunteers, they sufficed to show that six of the compounds were distinctly less active than quinine against the above infections. dose (2,26). SN-13,710 [2-(p-chlorophenyl)-7-chloro-a-(di-N-butylaminomethyl)-4-quinolinemethanol], one of the four derivatives examined only for tolerability, was also phototoxic (2).…”

Section: -Quinolinemethanol Antimalarials 1017mentioning

confidence: 99%

Antimalarial Activities of Various 4-Quinolinemethanols with Special Attention to WR-142,490 (Mefloquine)

Schmidt

Crosby

Rasco

et al. 1978

Pilot appraisals of the activities of a selected group of 4-quinolinemethanols against acute Plasmodium falciparum infections in owl monkeys indicated that compounds of this class are equally active against infections with chloroquine-resistant and chloroquine-susceptible strains and that this efficacy is not compromised by concomitant resistance to pyrimethamine, and in addition, identified three derivatives with outstanding activity (WR-226,253; WR-142,490; and WR-184,806). WR-142,490, the second 4-quinolinemethanol evaluated in the above model, was five times as active as chloroquine against infections with the chloroquine-susceptible, pyrimethamine-resistant strain and had a much larger therapeutic index. Expanded evaluations designed to support projected studies in human volunteers provided full confirmation of the pilot appraisals and in addition showed: (i) that the activity of WR-142,490 was a function of the total dose delivered, single doses being as effective as three or seven fractional doses administered over as many days; (ii) that intravenous administration of this agent was feasible and effective; and (iii) that the compound was at least as active against infections with P. vivax as against infections with P. falciparum . Companion studies in rhesus monkeys infected with P. cynomolgi showed that WR-142,490 lacked prophylactic or radical curative activity, but that it was as effective as chloroquine as a companion to primaquine in a combination curative drug regimen. The results of human volunteer and field trials agree well with comparable segments of these experimental evaluations.