Accession Number : ADA187365

Title :   Antimalarial Cyclic Peroxide Lactones.

Descriptive Note : Final rept. 15 Oct 84-28 Feb 87,

Corporate Author : NORTH CAROLINA UNIV AT CHAPEL HILL SCHOOL OF PHARMACY

Personal Author(s) : Lee, Kuo-Hsiung

PDF Url : ADA187365

Report Date : 31 May 1987

Pagination or Media Count : 48

Abstract : An alpha-santonin-derived cyclic peroxide (VI of Scheme-1) related to qinghaosu (1 of Scheme-4) has been synthesized and tested for antimalarial activity. The result indicates that the requirement of the cyclic peroxide function for potent antimalarial activity among the sesquiterpene lactones might be quite specific and could involve a unique carbon-oxygen linkage as found in qinghaou. One of the mechanisms of action of qinghaosu and artesunate was found to inhibit the activity of the cytochrome oxidase which is located on the plasma, the nuclear and the food vacuole limiting membranes as well as in the mitochondria of the trophozoites of Plasmodium berghei. The quassinoids bruceoside-A, brusatol and bruceolide were tested for antimalarial activity in vitro against the chloroquine-resistant (Smith) isolates of Plasmodium falciparum. Brusatol was quite active, bruceoside-A was not active, and bruceolide showed only a trace of activity. The fact that 15 (E)-non-2-enoyl bruceolide synthesized from brusatol was eight times less active than brusatol would indicate that the requirement of a C-15 ester moiety among brusatol related quassinoids for enhanced antimalarial activity could be quite specific. The semi-synthetic bruceoside-A acetonide and 15-methylcarbamoyl bruceolide were also found to be less active than brusatol. The antimalarial activity of 15-phenylalaninyl bruceolide is curently under evaluation. The antimalarial activity of these compounds will be evaluated shortly.

Descriptors :   *ANTIMALARIALS, *LACTONES, *PEROXIDES, CYTOCHROME OXIDASE, IN VITRO ANALYSIS, MITOCHONDRIA, PLASMODIUM BERGHEI, PLASMODIUM FALCIPARUM, POTENCY, TEST AND EVALUATION, SYNTHESIS(CHEMISTRY), CYCLIC COMPOUNDS

Subject Categories : Pharmacology

Distribution Statement : APPROVED FOR PUBLIC RELEASE