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

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: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 88%

Antischistosomal Activities of Mefloquine-Related Arylmethanols

Ingram

Ellis

Keiser

2012

“…This subgroup included 22 treated subjects and 3 untreated controls. The remaining 19 monkeys, all previously infected with the Oak Knoll strain of P. falciparum and cured via treatment with a 4-quinolinemethanol or 4-pyridinemethanol (11,13), were used for studies with the Palo Alto strain of P. vivax. Fifteen of the 19 (14 treated and 1 untreated control) were employed in the primary ANTIMICROB.…”

Section: Methodsmentioning

confidence: 99%

“…Second, resistance to floxacrine emerges rapidly, at a rate not less than that of proguanil or pyrimethamine (16,17), compounds that have presented resistance problems in field use. Third, by comparison, floxacrine is a weak competitor of a group of aminoalcohols which have been studied in depth in the same animal models (11)(12)(13)(14). Some have already exhibited promise in limited clinical trials (11,12).…”

mentioning

confidence: 99%

Antimalarial Properties of Floxacrine, a Dihydroacridinedione Derivative

Schmidt

1979

Self Cite

Evaluations of the activities of floxacrine [7-chloro-10-hydroxy-3-(4-trifluoromethylphenyl)-3,4-dihydroacridine-1,9(2H, 10H)-dione] in owl monkeys infected with trophozoites of a chloroquine-quinine-resistant strain of Plasmodium falciparum, a strain of this plasmodium resistant to both of these quinolines and pyrnmethamine, or a strain of P. vivax resistant only to pyrimethamine showed that: (i) this compound regularly effected temporary clearance of parasitemia at daily doses of 1.25 to 2.5 mg/kg; (ii) doses required for the cure of established infections were larger by factors of 6 to 64 than those that effected parasite clearance; (iii) there was more than a 10-fold difference in doses required for the cure of infections with the different strains; and (iv) resistance to floxacrine developed rapidly. Evaluations of the activities of floxacrine in rhesus monkeys challenged with sporozoites of P. cynomolgi showed that: (i) 0.625-mg/kg doses administered daily throughout the incubation period provided complete protection against infection; (ii) single 40.0-mg/kg doses delivered 2 h before sporozoite challenge were without prophylactic activity; and (iii) daily doses of 40.0 mg/kg, the maximum tolerated level, productive of a hemorrhagic syndrome in some subjects, would not cure established infections. These observations suggest that the potential contribution of floxacrine to malaria therapy would be limited to the prophylactic area and for practical reasons would be restricted there by the requirement for daily dosage.Floxacrine (Fig. 1) identical doses of this dihydroacridinedione derivative were required for the cure of infections with the drug-susceptible strain and strains resistadnt to chloroquine, pyrimethamine, and sulfadoxine; (iii) floxacrine was approximately twice as active when administered subcutaneously as when delivered orally; and (iv) irrespective of route of administration, the compound had a favorable therapeutic index; i.e., the ratio of the 50% lethal dose to the dose required to cure 50% of infections (LD5o/CD5o) was in excess

“…Enpiroline has demonstrated significant activity against both the chloroquine-susceptible and the multidrug-resistant forms of P. falciparum. In owl monkeys enpiroline phosphate exhibited a dose which cures 90% of the animals of approximately 30 mg/kg against the multidrugresistant Vietnam Smith strain of P. falciparum when administrated as a single oral dose on 3 consecutive days (17). In human studies enpiroline phosphate was effective against induced multidrug-resistant Vietnam Smith P. falciparum infections (3).…”

mentioning

confidence: 99%

Crystal and molecular structure of the antimalarial agent enpiroline

Karle

1989

To identify common spatial and structural features of amino alcohol antimalarial agents with the eventual goal of designing more effective drugs and a better understanding of the mechanism of action of this class of antimalarial agents, the three-dimensional crystal and molecular structure of enpiroline, a new antimalarial agent active against chloroquine-resistant Plasmodium falciparum, was determined by X-ray crystallography and compared with the crystal structures of the cinchona alkaloids and of the new antimalarial agent WR 194,965. The aromatic rings of the phenyl-pyridine ring system of enpiroline are twisted from each other by approximately 180. The intramolecular aliphatic N-O distance in enpiroline was 2.80 A (1 A = 0.1 nm), which is close to the N-O distance found in the antimalarial cinchona alkaloids. Enpiroline contains both an intramolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms and an intermolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms of two neighboring molecules. One enantiomer of enpiroline superimposed best with quinine, and the other enantiomer of enpiroline superimposed best with quinidine, suggesting that both enantiomers of enpiroline possess antimalarial activity. Since a common feature of the crystal structures of the amino alcohol antimalarial agents is the formation of intermolecular hydrogen bonds, the common spatial direction of hydrogen bond formation indicates the potential ability of these antimalarial agents to bind to a common receptor site. The crystallographic 1.46 g cm-3; source of radiation, CuKa (X = 1.54178 A); ,i (absorption coefficient) = 11.49 cm-'; F(000) (sum of atomic scattering factors at zero scattering angle) = 832; room temperature; final R = 8.7% for 1,798 reflections with FOI > 3of.With the continuing spread of multidrug-resistant Plasmodium falciparum malaria (14), the development of new antimalarial drugs is imperative. Enpiroline (Fig. 1, com falciparum infections (3).A detailed knowledge of the three-dimensional spatial requirements of the amino alcohol antimalarial agents should expedite the continued development of antimalarial drugs active against P. falciparum and provide clues to the mechanism of action of this class of antimalarial agents. The mechanism of action of quinoline-containing or amino alcohol or both antimalarial agents remains unknown (5,6,16). Alkalinization by antimalarial agents of parasite acid vesicles (11) appears to contribute to parasite toxicity, but does not provide a complete explanation of antimalarial activity due to the lack of direct correlation of pKas of the antimalarial * Corresponding author. agents with antimalarial activity and the unpredictability of the cross resistance of different parasite strains (4,5,16).Although the mechanism of antimalarial action of the amino alcohol antimalarial agents has not been determined, the activity of the amino alcohol antimalarial agents does have structural requirements, as exemplified by the active erythro cinchona alkaloids (quini...