Publication Date

2016-5

Document Type

Honors Thesis

Department

Biological Sciences

Keywords

Lymphatic filariasis, Elephantiasis, Drug development, Neurolaena labota, Jack-ass bitters, NTD (neglected tropical disease), Plant-based drug therapies, Central and South American indigenous plants, Filariasis-Treatment, Elephantiasis-Treatment, Lactones, Lobata, Vegetable materia medica

Abstract

Lymphatic filariasis (LF), a parasitic illness, is a globally neglected tropical disease that is known to keep 1.4 billion people at risk of infection, mostly in Southeast Asia and Africa (CDC, 2013). LF is a mosquito born disease that is caused by the human parasites: Wuchereria bancrofti, Brugia malayi, and Brugia timori. This study focuses on testing sesquiterpene lactones, called neurolenins, which are secondary plant metabolites from Neurolaena lobata, a medicinal herb, native to Guatemala and Central America. The Williams and Shea Laboratories together plan to modify neurolenin to improve its potential as a drug candidate that exhibits anti-filiarial activity against LF parasites. Current drug treatments for LF do not target adult parasites residing in human lymph nodes and vessels, and possible issues of genetic resistance necessitate exploration of drug candidates that target all life stages of the parasite including L3, adults, and microfilariae (mf). Neurolenin B, a sesquiterpene lactone from N. lobata, is biologically active in vitro against L3, adult, and mf B. pahangi and B. malayi nematodes. In this study, the Shea Laboratory converted Neurolenin D, another sesquiterpene lactone found in N. lobata, to Neurolenin B via acetylation and esterification methods that were analyzed for their efficacy in killing filarial parasites in culture. Using the acetylation technique, synthesized recrystallized Neurolenin B (modified from Neurolenin D) was biologically active with significant killing against adult female, adult male, L3, and mf B. malayi and B. paghangi parasites. The Neurolenin B product synthesized using an esterification procedure (modified from Neurolenin D), also called isovaleric acid Neurolenin D ester, was also biologically active with significant killing against L3 B. pahangi parasites. The ability for Neurolenin B to kill adult worms makes it a novel drug for LF because current drugs only target mf. Future investigation will continue with Ames testing to screen various forms of neurolenin for potential mutagenicity. Future work with the Shea Laboratory will also examine improvements in solubility for isovaleric Neurolenin D ester for further testing. Both acetylated and esterified Neurolenin B products will be tested against additional parasite cultures to validate the ability of these compounds to efficiently kill filarial nematodes. We also plan to use rodent models to compare the efficacy of the products in vivo in collaboration with Glaxo Smith Kline.

Language

English

Comments

57 pages : illustrations (some color). Honors project, Smith College, 2016. Includes bibliographical references (pages 54-57)

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