Defense Date

8-21-2020

Graduation Date

Fall 12-18-2020

Availability

Immediate Access

Submission Type

thesis

Degree Name

MS

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Kevin Tidgewell

Committee Member

Aleem Gangjee

Committee Member

Patrick Flaherty

Keywords

marine drug, cyanobacteria, malaria, Chagas, American trypanosomiasis, protozoa, Panama, non-ribosomal peptide, total synthesis, Leishmaniasis

Abstract

Millions of people die every year because of infectious diseases, and malaria is among the top five of the deadliest infectious disease. In 2018, malaria took more than four hundred thousand lives, and more than half of them are children under five years of age. Most malaria-affected parts of the world are also the home of the most underprivileged people. Seemingly, antimalarial drug discovery never achieved the attraction that it requires. Like malaria, another infectious disease that is not extensively explored by drug discovery campaigns is American trypanosomiasis or Chagas disease. More than a hundred years have passed since discovering the disease, and surprisingly only two drugs are clinically available; both are far from ideal. It is imperative to say that these disease areas require more attention from drug discovery researchers. Hence, my project focuses on drug discovery for these neglected diseases utilizing one of the most prolific sources for lead molecule generation, marine cyanobacteria.

This thesis describes the discovery of an N-methylated peptide, naranjamide, from a marine cyanobacterium collected in the Portobelo National Park, Panama. The compound inhibited the growth of Trypanosoma cruzi and Plasmodium falciparum parasites. To confirm the structure and established its antiparasitic potential, I attempted to synthesize the molecule and found the synthetic version to inhibit both T. cruzi and P. falciparum parasite with IC50 values of 9.2 μM and 2.8 μM, respectively. Later, a series of non-methylated analogs were synthesized, which are found to be malaria selective. A more detailed study is required to establish a complete structure-activity relationship.

Language

English

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