Abstract

Malaria kills over 500,000 people each year and over a third of the global population is at risk of infection. Though the human race has been fighting the malaria war for over 4,000 years and we have made great strides in eliminating malaria from many countries, we are treading on the edge of what could be another malaria epidemic primarily due to widespread drug resistance. There are documented cases of resistance for every known antimalarial in use today, including Artemisinins. It is critical that we open a new window of discovery in development of next generation antimalarials that circumvent current resistance paradigms. These compounds must attack new targets, have different speeds of action, and ideally possess powerful transmission blocking potential if they are to be successful antimalarial candidates. Screening endeavors historically focused on either synthetic or natural product libraries. Recent efforts have focused on combining privilege elements of natural products into synthetically tractable compounds to create hybrid libraries. To discover novel antimalarial pharmacophores, we have screened natural products derived from marine biodiversity as well as natural product-inspired synthetic libraries. Our phenotypic screening of 3,164 marine natural products from the Harbor Branch Oceanographic Institute, 56 high density combinatorial natural product based libraries from the Torrey Pines Institute for Molecular Studies, alkaloid, terpene, and macrocyclic libraries from Memorial Sloan Kettering Cancer Center, and 594 natural product inspired compounds from Asinex have identified several new selective antiplasmodial hit chemotypes. In this study, we have focused on compounds that exhibit cellular actions differing from current antimalarials. Two of the scaffolds, UCF 201 and 501, a spirocyclic chromane and a nitroquinoline, respectively, act early in the development cycle and block invasion. The alkaloid derived compound M03 blocks egress. UCF 501 cures malaria in the rodent model and significantly inhibits stage V gametocytogenesis. Given that discovery of transmission blocking agents are a priority in the malaria elimination strategies, this result is significant. This work is of high impact as it addresses a critical need in the field- next generation antimalarial scaffolds for malaria therapy and elimination campaign.

Notes

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Graduation Date

2017

Semester

Summer

Advisor

Chakrabarti, Debopam

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences

Format

application/pdf

Identifier

CFE0006785

URL

http://purl.fcla.edu/fcla/etd/CFE0006785

Language

English

Release Date

8-15-2022

Length of Campus-only Access

5 years

Access Status

Doctoral Dissertation (Open Access)

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