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Antimicrobial Agents and Chemotherapy, December 2006, p. 4132-4143, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00631-06

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, Maryland 20910,¹ Division of Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, Maryland 20910,² Department of Veterinary Medicine, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, 315/6, Rajthevi, Bangkok, Thailand 10400,³ Tropical Medicine Research/Gorgas Memorial Research Institute, Ave. Justo Arosemena no. 3530, Panama City, Panama⁴

Received 23 May 2006/ Returned for modification 8 July 2006/ Accepted 30 August 2006

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 The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s.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.

Published ahead of print on 11 September 2006.