- Title
- Identification of antikinetoplastid compounds from Psorothamnus polydenius and P. arborescens
- Author
- Salem Hemida, Manar Mahfouz
- Degree
- Doctor of Philosophy, Ohio State University,
Pharmacy, 2005.
- Advisor
- Karl A. Werbovetz
- Pages
- xx, 214 p. : ill (some col.)
- Abstract
- Parasitic diseases such as leishmaniasis and trypanosomiasis remain a major public health problem. Common chemotherapeutic agents currently used are often inadequate, requiring long courses of parenteral administration, having toxic side effects or are becoming less effective due to the emergence of resistant strains. Thus, there is an urgent need for new, effective, and inexpensive drugs. The goal of our research is to identify effective antileishmanial and trypanocidal agents from plant sources using a systematic approach. We screened a natural products library of a representative diversity for antiparasitic activity and selectivity against Leishmania donovani and Trypanosoma brucei. From the results, the plant genus Psorothamnus was identified as a promising source of potential new antiparasitic compounds. Bioactivity-guided fractionation of the methanolic extract of Psorothamnus polydenius yielded the new chalcone, 2,2′,4′-trihydroxy-6′-methoxy-3′,5′-dimethylchalcone , together with six other known compounds, 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone, dalrubone, demethoxymatteucinol, eriodictyol, oleanolic acid and photodalrubone. The isolated compounds were evaluated for their leishmanicidal and trypanocidal properties. Dalrubone displayed significant activity against intracellular L. donovani amastigotes. Flow cytometry analysis showed that dalrubone does not affect the cell cycle progression of the parasite. Electron microscopy revealed significant ultrastructural changes in the parasite suggesting perturbations in the secretory pathways of the parasite. However, dalrubone did not display a favorable in vivo activity against L. donovani infection in mice, possibly because of a low potency or unfavorable pharmacokinetics. Bioactivity-guided fractionation of the root extract of P. arborescens yielded the new isoflavone 5,7,3΄,4΄-tetrahydroxy-2΄-(3,3-dimethylallyl)isoflavone and the new 2-arylbenzofuran 2-(2΄-hydroxy-4΄,5΄-methylenedioxyphenyl)-6-methoxybenzofuran-3-carbaldehyde, together with seven other known compounds, fremontin, glycyrrhisoflavone, calycosin, maackiain, 4-hydroxymaackiain, oleanolic acid, and isoliquiritigenin. The structure of the isoflavone fremontin was revised using spectroscopic and chemical methods and was assigned a new structure. The isolated compounds, in addition to a small set of related isoflavones, were assessed for their antiparasitic activity and the isoflavone template was identified as a promising antitrypanosomal scaffold. The mechanism of the antikinetoplastid activity of isoflavonoids is not clear although electron microscopy studies revealed significant ultrastructural changes of mitochondria in isoflavone-treated L. donovani promastigotes.
- Subject Headings
- Health Sciences, Pharmacy
- Keywords
- Natural products; Psorothamnus polydenius; Psorothamnus arborescens; Kinetoplastid parasites; Leishmania; Trypanosoma
Document number: osu1127103915.
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Copyright 2005, all rights reserved.
