ORCID

0000-0002-6146-5309

Keywords

ring distortion, malaria, Plasmodium falciparum, indole alkaloid, antiplasmodials, novel, drug discovery reserpine

Abstract

Drug resistance is a prevalent challenge in the eradication of malaria, a devastating infection caused by species of the obligate intracellular protozoan parasite, Plasmodium. To mitigate the threat of emerging resistance to the antimalarials currently available, new screening libraries are needed to discover novel chemotypes. Compound collections of commercial or “in-house” origin are often limited in diversity and stereochemical complexity. To address the lack of chemical diversity in current drug discovery efforts, we have utilized an innovative “complexity-to-diversity” ring distortion approach to rapidly generate a diverse and unique library of complex small molecules from stereochemically complex indole alkaloids. Through the process of ring distortion, the complex ring systems of natural products are re-engineered via ring fusion through various chemical transformations. Previous work in our laboratory has shown success in generating antiplasmodial compounds through the ring distortion of vincamine and yohimbine – transforming inactive parent compounds into products with submicromolar EC50 values against the multidrug-resistant Dd2 parasite line, along with excellent selectivity. Applying the ring-distortion approach on parent compound reserpine, we synthesized and tested two libraries of 433 compounds for antiplasmodial activity and selectivity. Based on this screening, structural optimization was pursued with the top compound MG-2-75. From these efforts, reserpine derivatives AB-2-155, AB-2-81, AB-1-163, AB-2-115, and AB-1-73 have all displayed potent antiplasmodial activity and high selectivity, with EC50 values ranging from 46 nM to 140 nM. Of these ring distorted compounds, AB-2-155 displayed the lowest EC50 (46 ± 5 nM) and highest selectivity (SI > 289). These hit compounds were further explored in vitro to assess their killing profiles and asexual blood stage activity. All these hits showed a moderate killing profile in Pf3D7, and they appear to inhibit the early blood stages (ring and trophozoite) of the parasite. AB-2-155 and AB-2-81 also exhibit promising liver stage activity. To determine a mechanism of action and possible targets of AB-2-155, resistance line generation experiments and a cellular thermal shift assay (CETSA) were performed. After undergoing four months of in vitro evolution of resistance, the highest fold change that occurred under drug pressure with AB-2-155 was only 1.3, suggesting that the compound is refractile to resistance development. CETSA data highlights an essential protein, Ferlin-like protein, to be a possible target of AB-2-155. These findings validate the utility of ring distortion to re-engineer natural products for the development of a new class of dual-stage active antiplasmodials.

Completion Date

2025

Semester

Summer

Committee Chair

Chakrabarti, Debopam

Degree

Master of Science (M.S.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Release Date

8-15-2027

Document Type

Thesis

Campus Location

Orlando (Main) Campus

Subjects

Antiparasitic agents--Design; Alkaloids--Research; Malaria--Research; Malaria--Chemotherapy; Drug resistance--Research

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Available for download on Sunday, August 15, 2027

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