Document Type

Thesis - Open Access

Award Date

2024

Degree Name

Master of Science (MS)

Department / School

Pharmaceutical Sciences

First Advisor

Tanvir Khaliq

Abstract

Leishmaniasis is a protozoan parasitic disease caused by the species Leishmania that affects millions of people around the world. It is a serious public health concern in the developing world with about 1 million cases and 70,000 fatalities occurring each year. It has several forms with visceral, and cutaneous leishmaniasis being the most common forms of the disease. Visceral leishmaniasis, caused by the Leishmania donovani occurs mainly in Brazil, Eastern Africa, and India, and is fatal if left untreated. The current treatments for leishmaniasis such as pentavalent antimonials, amphotericin B, miltefosine, paromomycin, pentamidine, and some azoles suffer from serious drawbacks. Examples are parasitic resistance, toxicity, reduced efficacy, cost, longer duration, and except for miltefosine, have routes of administration incompatible with the settings where the disease is endemic. Therefore, new, safe, short, and orally acting drugs are urgently needed to effectively treat leishmaniasis. We have identified a pyrroloquinazoline alkaloid natural product lead peganine from Peganum harmala that shows promising activity against visceral leishmaniasis. It selectively inhibits the growth of the intracellular L. donovani parasites, amastigotes without significant toxicity to the host macrophages. Preliminary studies have shown that peganine inhibits L. donovani topoisomerase 1 with a unique mechanism of action different from the known DNA-topoisomerase 1 inhibitor, camptothecin. Most importantly, it significantly reduces the parasitic burden in hamsters infected with visceral leishmaniasis infection following oral administration. However, peganine shows in vivo efficacy at a relatively high dose, therefore, structural modification of the lead molecule is necessary to optimize its antileishmanial activity. Our laboratory is focused on the design, synthesis, and evaluation of biological activity of novel analogs of peganine to explore their structure-activity relationships (SARs) and identify novel analogs with improved antileishmanial activity. We have used scaffold hopping drug design strategy to design a novel scaffold of peganine for synthesis and evaluation of its antileishmanial activity. We have replaced the core benzenoid ring of peganine with a pyridine ring to enhance the hydrogen bonding interactions with the target enzyme and improve the antileishmanial activity of the new scaffold. The total synthesis of the analog was accomplished up to the penultimate step in moderate to excellent yields. The intermediaries were characterized by mass spectrometry and Nuclear Magnetic Resonance (NMR). The synthesis of the final step is being carried out to obtain the target molecule.

Library of Congress Subject Headings

Leishmaniasis -- Treatment.
Parasitic diseases.
Drugs -- Design.
Drugs -- Structure-activity relationships.
Quinazoline.
Alkaloids.

Publisher

South Dakota State University

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Rights Statement

In Copyright