X-ray crystal structure of the antimalarial agent (-)-halofantrine hydrochloride supports stereospecificity for cardiotoxicity.
Abstract
X-ray crystal structure of the antimalarial agent (-)-halofantrine hydrochloride supports stereospecificity for cardiotoxicity. J M Karle Department of Pharmacology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA. ABSTRACT The crystal and molecular structures and absolute configuration of (-)-halofantrine hydrochloride were determined by X-ray diffraction. The absolute configuration of the single chiral center of (-)-halofantrine was established to be in the S configuration. Thus, (+)-halofantrine, the more cardiotoxic isomer, has the R configuration. The carbon atom adjacent to the aromatic ring has the same configuration in both (+)- halofantrine and quinidine, suggesting a stereospecific component to the cardiotoxicity produced by both agents. The intramolecular N ... O distance is 4.177 +/- 0.006 A (1 A = 0.1 nm), which is close to the N ... O distance found in the crystal structure of (+/-)-halofantrine hydrochloride, even though the N-H group points in opposite directions in racemic halofantrine and (-)-halofantrine. Both the hydroxyl group and the amine group form hydrogen bonds with the chloride anions. The crystallographic parameters for (-)-halofantrine hydrochloride were as follows: chemical formula, C26H31Cl2F6NO+. Cl-; Mr, 492.4; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a was 6.290 +/- 0.001 A, b was 13.533 +/- 0.003 A, and c was 30.936 +/- 0.006 A; volume of the unit cell, 2,633.2 +/- 0.7 A(3); number of molecules per unit cell, 4; calculated density, 1.354 g cm(-3); source of radiation, Cu K(alpha) (lambda = 1.54178 A); mu (absorption coefficient), 3.50 mm(-1); F(000) (sum of atomic scattering factors at zero scattering angle), 1,120; room temperature was used; final R (residual index), 4.75% for 2,988 reflections, with absolute value of Fo > 3sigma(F), where Fo is the observed structure factor and F is the structure factor. CiteULike Connotea Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter What's this? « Previous | Next Article » Table of Contents This Article Antimicrob. Agents Chemother. April 1997 vol. 41 no. 4 791-794 » Abstract PDF Services Email this article to a colleague Similar articles in ASM journals Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of AAC Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Load citing article information Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Karle, J. M. Search for related content PubMed PubMed citation Articles by Karle, J. M. Related Content Load related web page information Social Bookmarking CiteULike Connotea Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter What's this? current issue December 2011, volume 55, issue 12 Alert me to new issues of AAC About AAC Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy AAC RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0066-4804 Online ISSN: 1098-6596 Copyright © 2011 by the American Society for Microbiology. For an alternate route to AAC .asm.org, visit: http://intl- AAC .asm.org | More Info» var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); var pageTracker = _gat._getTracker("UA-5821458-3"); pageTracker._trackPageview();