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Phytochemical Investigation of the Medicinal Plant Taxodium distichum and Library Screening of Thalictrum Alkaloids for New Antileishmanial Drug Leads

Naman, Charles Benjamin
http://orcid.org/0000-0002-4361-506X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429283826

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmacy.
Leishmaniasis is an infectious disease caused by blood-borne parasites from the genus Leishmania. The therapeutic options currently available for this potentially deadly and disfiguring disease are limited in their number and availability to at-risk populations, and also cause severe toxicity and side effects. An increasing incidence of drug resistance has also been developing among clinical strains of Leishmania parasites. There is thus a great need for the discovery and development of new antileishmanial agents. Natural products research has historically been a successful avenue for the discovery of new drugs and lead molecules for medicinal chemistry optimization efforts. This may be because natural products tend to be structurally complex and suited for interaction with various drug targets in biological systems. Through collaborative studies on the in vitro antileishmanial activities of plants growing in Ohio, the extract produced from bald cypress (Taxodium distichum) cones was found to be active and was selected for phytochemical investigation. Additionally, a chemically diverse set of 234 molecules in a library of previously isolated plant natural products was tested against L. donovani, which is responsible for the fatal (visceral) manifestation of leishmaniasis. T. distichum cone extract has been used in traditional medicine practices for many indications, such as treatment of the parasitic disease, malaria. The bioactivity-guided fractionation of this extract has led to the observation of in vivo activity of one crude subfraction of the chloroform partition (TDCD3F2), in mice infected with L. donovani. Several new molecules were isolated from this sample, including a para-benzoquinone containing abietane diterpenoid (103), a para-benzoquinone containing seco-abietane diterpenoid (105), and two rearranged abietane diterpenoids (109 and 110), along with 12 previously known compounds. These molecules were tested for their antileishmanial activities, of which nine were active against L. donovani promastigotes in vitro, and the most potent were 41 (IC50 = 1.6 µM) and 105 (IC50 = 6.9 µM). The high yield of these bioactive natural products from an in vivo-active crude fraction of T. distichum cone extract suggested that these compounds and this extract represent potential leads for future antileishmanial drug discovery and development. The biological testing of a plant-derived natural product sample library led to the observation of in vitro activity against L. donovani promastigotes from three bisbenzyltetrahydroisoquinoline alkaloids (125-127) that were isolated previously, from Thalictrum alpinum. The first full spectroscopic studies of 125-127 were conducted to confirm their identities. The most promising in vitro test sample was 125, with an IC50 = 0.28 µM against L. donovani promastigotes and 29.3–fold selectivity versus its cytotoxicity to HT-29 mammalian colon cancer cells. This compound was accordingly tested in vivo using a mouse model of visceral leishmaniasis, and led to a dose-dependent reduction of the parasite burden in the murine livers and spleens without overt toxicity effects when administered intravenously at 2.8, 5.6, and 11.1 mg/kg per animal. This represents the first report of a bisbenzyltetrahydroisoquinoline alkaloid with in vivo efficacy against visceral leishmaniasis. Accordingly, compound 125 can be suggested as a promising lead molecule for antileishmanial drug discovery and development.
A. Douglas Kinghorn (Advisor)
Esperanza J. Carcache de Blanco (Committee Member)
James R. Fuchs (Committee Member)
305 p.
Chemistry; Medicine; Pharmacy Sciences
bioassay-guided fractionation; leishmaniasis; natural product; Taxodium distichum; abietane diterpenoid; Thalictrum alpinum; bisbenzyltetrahyroisoquinoline alkaloid;

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Citations

  • Naman, C. B. (2015). Phytochemical Investigation of the Medicinal Plant Taxodium distichum and Library Screening of Thalictrum Alkaloids for New Antileishmanial Drug Leads [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429283826

    APA Style (7th edition)

  • Naman, Charles. Phytochemical Investigation of the Medicinal Plant Taxodium distichum and Library Screening of Thalictrum Alkaloids for New Antileishmanial Drug Leads. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429283826.

    MLA Style (8th edition)

  • Naman, Charles. "Phytochemical Investigation of the Medicinal Plant Taxodium distichum and Library Screening of Thalictrum Alkaloids for New Antileishmanial Drug Leads." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429283826

    Chicago Manual of Style (17th edition)

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