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

Schmidt, L. H.; Crosby, Ruth; Rasco, Jane F.; Vaughan, Dennis

doi:10.1128/aac.13.6.1011

Cited by 72 publications

(48 citation statements)

References 33 publications

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“…On the basis of these pilot appraisals and a critical comparative study which showed that WR- (25,26). Second, WR-172,435 and WR-180,409 effect parasite clearance slightly more rapidly tharr mefloquine (25) and much more rapidly than the two phenanthrenemethanols (26) in the various owl monkey models.…”

Section: Discussionmentioning

confidence: 99%

“…The phosphate salt of WR-180,409 was also used in appraising the feasibility of administering this compound intravenously and its efficacy when so delivered. The procedures for preparing solutions of WR-172,435 and WR-180,409 for administration via the oral route and of the latter compound for intravenous delivery were identical with those employed with mefloquine (25).…”

mentioning

confidence: 99%

“…' The data on which these calculations were based were acquired by the (23,25), both compounds were distinctly more active against infections with the Palo Alto strain of P. vivax than against infections with the Smith strain of P. fakciparum.…”

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confidence: 99%

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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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Section: Discussionmentioning

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confidence: 99%

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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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“…Consequently, chloroquine resistance in this model may be attributed to reduced exposure of the parasites rather than to ineffectiveness of the drug after it reaches the parasites: This mechanism of resistance provides a basis for explaining how drugs in the same chemotherapeutic class with chloroquine could be effective in the treatment of chloroquine-resistant malaria. For example, amodiaquine, quinine, and mefloquine might have exactly the same, albeit unknown, mechanism of action as chloroquine (2) and yet be more effective in the treatment of chloroquine-resistant malaria (1,13,(16)(17)(18)(19)(20)(21) because they penetrate to the parasites. These four drugs all are quinoline derivatives and have many characteristics in common, but they also possess t Contribution 1521 from the Army Research Program on malaria.…”

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confidence: 99%

“…We now report that mefloquine accumulation is undiminished in erythrocytes infected with P. berghei CR. Mefloquine is a new antimalarial drug (15) that is more effective than chloroquine against P. berghei CR (16) and P. falciparum CR (1,13,(17)(18)(19)21).…”

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Chloroquine Resistance in Malaria: Accessibility of Drug Receptors to Mefloquine

Fitch

Chan

Chevli

1979

Antimicrob Agents Chemother

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The process of mefloquine accumulation was studied in mouse erythrocytes infected with either Plasmodium berghei CS (chloroquine susceptible) or P. berghei CR (chloroquine resistant). In both cases, mefloquine was accumulated by a saturable process with an apparent dissociation constant of 2.5 x 106 M and an apparent maximal capacity of 700 ,umol per kg of erythrocyte pellet; uninfected mouse erythrocytes accumulated more than half as much mefloquine as infected erythrocytes. The process of accumulation was not stimulated by providing glucose as a substrate, and it was not inhibited in infected erythrocytes by azide, iodoacetate, or incubation at 2°C. Although mefloquine was accumulated more effectively than chloroquine by uninfected erythrocytes and by erythrocytes infected with P. berghei CR, competition between chloroquine and mefloquine was observed, raising the possibility that the same process of accumulation serves both drugs. Chloroquine competitively inhibits mefloquine accumulation, with an apparent inhibitor constant of 1.7 x 10-3 M, and mefloquine competitively inhibits chloroquine accumulation, with an apparent inhibitor constant of 2 x 10' M.The same process of accumulation and the same group of receptors could serve both drugs if mefloquine has greater access than chloroquine to the receptors.Regardless of whether the same process serves both drugs, undiminished accumulation by erythrocytes infected with P. berghei CR provides an explanation for the superiority of mefloquine in treating chloroquine-resistant malaria.

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Natural Products as Leads for New Pharmaceuticals

Buss

Cox

Waigh

2003

Burger's Medicinal Chemistry and Drug Discovery

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A review of the use of natural products as starting points in the search for new pharmaceuticals, covering the broad areas of “Drugs affecting the centeral nervous system, ” “Neuromuscular blocking drugs,” “Anticancer drugs,” “Marine sources,” “Antibiotics,” “Cardiovascular drugs,” “Antiasthma drugs,” and “Antiparasitic drugs.” The review covers more than 100 years of development, from “old” drugs, such as morphine and quinine, to very recent discoveries, such as conotoxin and galantamine, and includes a discussion of the attributes of natural products as leads in the drug discovery process. Between 1990 and 2000, a total of 41 drugs derived from natural products were launched on the market by major pharmaceutical companies. In the chosen examples, the process of drug development is traced from the discovery of the activity of the natural compound, through chemical modification and biological evaluation, to either success or failure as a clinical product, highlighting the very different pathways to innovation that occur in each product.

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

Cited by 72 publications

References 33 publications

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

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

Chloroquine Resistance in Malaria: Accessibility of Drug Receptors to Mefloquine

Natural Products as Leads for New Pharmaceuticals

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