The relationship of physico-chemical properties and structure to the differential antiplasmodial activity of the cinchona alkaloids


Warhurst, DC; Craig, JC; Adagu, IS; Meyer, DJ; Lee, SY; (2003) The relationship of physico-chemical properties and structure to the differential antiplasmodial activity of the cinchona alkaloids. Malar J, 2. p. 26. ISSN 1475-2875 DOI: 10.1186/1475-2875-2-26

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Abstract

BACKGROUND: The 8-amino and 9-hydroxy substituents of antimalarial cinchona alkaloids have the erythro orientation while their inactive 9-epimers are threo. From the X-ray structures a 90 degrees difference in torsion angle between the N1-H1 and C9-O12 bonds in the two series is believed to be important. In order to kill the malaria parasite, alkaloids must cross the erythrocyte and parasite membranes to accumulate in the acid digestive vacuole where they prevent detoxication of haematin produced during haemoglobin breakdown. METHODS: Ionization constants, octanol/water distribution and haematin interaction are examined for eight alkaloids to explain the influence of small structural differences on activity. RESULTS: Erythro isomers have a high distribution ratio of 55:1 from plasma to the erythrocyte membrane, while for the more basic threo epimers this is only 4.5:1. This gives an increased transfer rate of the erythro drugs into the erythrocyte and thence into the parasite vacuole where their favourable conformation allows interaction with haematin, inhibiting its dimerization strongly (90 PlusMinus; 7%) and thereby killing the parasite. The threo compounds not only enter more slowly but are then severely restricted from binding to haematin by the gauche alignment of their N1-H1 and C9-O12 bonds. Confirmatory molecular models allowed measurement of angles and bond lengths and computation of the electronic spectrum of a quinine-haematin complex. CONCLUSION: Differences in the antiplasmodial activity of the erythro and threo cinchona alkaloids may therefore be attributed to the cumulative effects of lipid/aqueous distribution ratio and drug-haematin interaction. Possible insights into the mechanism of chloroquine-resistance are discussed.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: Malaria Centre
PubMed ID: 14505493
Web of Science ID: 186358700007
URI: http://researchonline.lshtm.ac.uk/id/eprint/15795

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