Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Abstract

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 The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s.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.In the late 1960s to early 1970s, Plasmodium falciparum malaria in Southeast Asia had begun to develop resistance to all of the available antimalarial drugs (6). Cure rates were 11 to 20% and 26 to 50% for chloroquine and quinine, respectively, and had declined to only 90% for the triple combination of quinine/pyrimethamine/dapsone (6). All of these regimens were associated with adverse side effects (6). As a consequence, the U.S. Army began routinely employing two experimental antimalarial drugs, WR030090 and WR033063, for the treatment of recrudescent malaria infections at the Walter Reed Army Medical Center (6). Subsequent field trials demonstrated that WR030090, a quinolinyl methanol, exhibited cure rates of at least 88% and was better tolerated than quinine (6, 21).Shortly thereafter, mefloquine was discovered and was developed commercially by Hoffman La Roche and the U.S. Army. Mefloquine exhibited a long half-life in humans, and this desirable property facilitated its administration as a single dose for malaria treatment and as a once-weekly dosing for prophylaxis (50). In contrast, WR030090 was only partially effective as a prophylactic agent, required a dosing regimen similar to that of quinine to effect cures, and was subsequently abandoned (6,9,21,30). However, it is important to recognize that this occurred because of unfavorable pharmacokinetic characteristics, not as a consequence of unacceptable toxicity.Mefloquine combined with artesunate constitutes one of the most effective combination agents for treatment of malaria (41). Mefloquine is also the only once-weekly drug approved for malaria chemoprophylaxis in the United States that...

Adaptation of a Thai Multidrug-Resistant C2A Clone of Plasmodium falciparum to Aotus Monkeys and Its Preliminary in vivo Antimalarial Drug Efficacy-Resistance Profile

“…49 We know from previous studies that a single oral dose of 20 mg/kg of MQ cures P. falcparum Vietnam oak knoll (FVO) infections in intact Aotus monkeys. 27 It is also known that MQ resistance may be caused by increased copy numbers of the pfmdr1 gene amplified during infection. 27 It is therefore possible that the resistance observed in this experiment may have been induced by the host immune response forcing the parasite to use its tremendous adaptation plasticity to enter into different physiologic stages before becoming completely adapted to growth within the Aotus .…”

“…27 It is also known that MQ resistance may be caused by increased copy numbers of the pfmdr1 gene amplified during infection. 27 It is therefore possible that the resistance observed in this experiment may have been induced by the host immune response forcing the parasite to use its tremendous adaptation plasticity to enter into different physiologic stages before becoming completely adapted to growth within the Aotus . 50 In conclusion, it appears that a MDR C2A clone of P. falciparum from Thailand has been successfully adapted to growth within spleenectomized Aotus monkeys.…”

“…6 For more than 40 years, the Panamanian Aotus ( Aotus lemurinus. lemurinus ) has been used to adapt new strains of malaria [7][8][9] study its biology, [10][11][12] pathogenesis of its infection, [13][14][15] and to test the efficacy and pharmacokinetics of antimalarial compounds [16][17][18][19][20][21][22][23][24][25][26][27] against these new strains. More recently, this model has also been used to test the efficacy and immunogenicity of antimalarial vaccines through the use of repeated challenge, 28 plasmid DNA vaccines, [29][30][31][32] temperature-sensitive mutants, 33 synthetic peptides, 34 recombinant proteins, [35][36][37] and even to test the immunogenicity of hepatitis B DNA vaccines.…”

Antimalarial Activity of Phenylthiazolyl-Bearing Hydroxamate-Based Histone Deacetylase Inhibitors

“…The antimalarial activity of WR301801 alone and in combination with chloroquine against blood stage Plasmodium berghei in mice and P. falciparum in Aotus lemurinus lemurinus monkeys was evaluated as described by us in an earlier publication (13). Briefly, in the mouse assay, all mice were inoculated intraperitoneally with 10 6 P. berghei-parasitized erythrocytes.…”

“…The half-life of WR30801 in mouse and human liver microsomes was determined as described in our earlier study (13).…”