Antimalarials. 2. 2,6-Bis(aryl)-4-pyridinemethanols

Blumbergs, Peter; Lamontagne, M. P.; Markovac, A.; Moehring, J. G.; Ash, A. B.; Stevens, Calvin L.

doi:10.1021/jm00278a006

Cited by 10 publications

(10 citation statements)

References 2 publications

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“…The title compound was prepared in one step from 3-benzoylacrylic acid and N-phenacylpyridinium bromide in the presence of excess ammonium acetate (Blumbergs et al, 1972). The compound was recrystallized from hot acetic acid as pale-yellow crystals.…”

Section: Methodsmentioning

confidence: 99%

2,6-Diphenylpyridine-4-carboxylic acid

Crispini

Neve

2001

Acta Crystallogr C

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Section: Methodsmentioning

confidence: 99%

2,6-Diphenylpyridine-4-carboxylic acid

Crispini

Neve

2001

Acta Crystallogr C

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“…In each case, the requisite quantity of W`R-180,409 was infused slowly and steadily over a 2-min period. Doses of 40.0 and 60.0 mg/kg were lethal, respiratory failure and cardiac arrest occurring in both subjects within 4 (iii) Incidental observations. The results of daily examinations of thick and thin blood films, a routine in all therapeutic studies, showed that WR-172,435 and WR-180,409 had dramatic effects on the morphology and numbers of the parasites within 24 h of initial dosage.…”

mentioning

confidence: 97%

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

Schmidt

Crosby

Rasco

et al. 1978

Antimicrob Agents Chemother

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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

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“…Conversion of the acid halide to the ␣-halo ketone could be accomplished through the diazoketone (1,19,25,26). Treatment of the ␣-halo ketone with sodium borohydride should afford the epoxide (3,29). Lastly, the epoxide could be opened with dibutyl amine to give an enantiomeric secondary alcohol (4,18,33).…”

Section: Methodsmentioning

confidence: 99%

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Dow

Heady

Bhattacharjee

et al. 2006

Antimicrob Agents Chemother

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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...

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Antimalarials. 2. 2,6-Bis(aryl)-4-pyridinemethanols

Cited by 10 publications

References 2 publications

2,6-Diphenylpyridine-4-carboxylic acid

2,6-Diphenylpyridine-4-carboxylic acid

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

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

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