Publication Date

2019

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Biochemistry

Advisors

Steven A. Willliams

Keywords

Lymphatic filariasis treatment, N. lobata, Mutagenicity, Toxicity testing, Medicinal chemistry

Abstract

Lymphatic filariasis is a neglected tropical disease (NTD) infecting over 120 million people worldwide. Current treatment and elimination efforts rely on mass drug administration (MDA) guided by the World Health Organization. These drugs, however, do not target adult nematodes, leading to a need for new antifilarial drug candidates that are more effective in eliminating adult nematodes already present in the human body. This is particularly important since it is the adult stages of the parasite that cause most pathogenicity in the human host and are responsible for production of microfilariae that transmit the disease via mosquito vectors. We are investigating the anti-adult killing activity of sesquiterpene lactones from the medicinal plant Neurolaena lobata. These compounds were tested on adult Brugia pahangi nematodes using an in vitro culturing procedure. The most effective derivatives were found to be neurolenin B, acetylated neurolenin C, and propionic esterified neurolenin B which all reached complete mortality of both adult female and adult male parasites within 96 hours of treatment. After determining significant antifilarial activity, the next steps in developing a potential drug candidate are to evaluate both the relative toxicity and mutagenic effects of neurolenin B and other effective neurolenin derivatives. The Ames test is the most universally accepted biological assay used to determine mutagenicity for a given compound and we have demonstrated that neurolenin has low mutagenicity using this assay. Additionally, we have cultured hepatic HepaRG cells and performed the MTT assay to identify if neurolenin derivatives exhibit cellular toxicity. With the demonstrated activity of these neurolenin derivatives against B. pahangi, and their low level of cellular mutagenicity and toxicity, we have identified a potential drug candidate for lymphatic filariasis and potentially other nematode-caused neglected tropical diseases. Since these molecules show excellent biological activity against adult parasites, they may prove to be the macrofilaricides long-sought by the World Health Organization.

Rights

©2019 Lydia Pedrick DeAngelo. Access limited to the Smith College community and other researchers while on campus. Smith College community members also may access from off-campus using a Smith College log-in. Other off-campus researchers may request a copy through Interlibrary Loan for personal use.

Language

English

Comments

148 pages : color illustrations. Includes bibliographical references (pages 140-148)

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