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Please use this identifier to cite or link to this item: http://arks.princeton.edu/ark:/88435/dsp01dn39x389f
Title: Design and Synthesis of Two Different Antimalarial Classes for the Topical Treatment of Cutaneous Lupus Erythematosus and the Structure-Activity Relationship of Novel Spiroindolones
Authors: Mai, Nicholas
Advisors: Reider, Paul J.
Department: Chemistry
Class Year: 2015
Abstract: Antimalarial drugs are a broad spectrum of pharmaceutical agents that have been used to treat malaria for centuries and, more recently, have been found to be effective in treating Cutaneous Lupus Erythematosus (CLE), a dermatological autoimmune disease. This project focuses on the development of novel therapeutic agents for these two diseases. For CLE, we focused on improvement of hydroxychloroquine, while, for malaria, we focused on further development of the novel spiroindolone class. Hydroxychloroquine (HCQ) has been shown to be effective at treating the symptoms of CLE, however, only oral formulations of the drug are available, causing significant side effects (most notably retinopathy) when used for long portions of time due to its subsequent presence in the systemic circulation. Our work focused on the creation of esterified prodrugs of HCQ that would increase the molecule’s otherwise low logP and skin permeability. By easing this burden on the formulations problem, we hoped to make progress towards a topically bioavailable HCQ-based cream that would allow direct application to skin affected by CLE, thus increasing effectiveness and decreasing overall side-effects. The synthesis of a wide array of different compounds was successful, but further biological and physicochemical data is still pending. The spiroindolone class of antimalarials is a completely novel class with high efficacy and a favorable pharmacokinetic profile. Novartis, who had first discovered the class, developed and optimized a candidate that they pushed to clinical trials, but a lot of the spiroindolone’s chemical space was left unexplored. As a result, our work focused on investigating the structureactivity relationship (SAR) at the so-called “C3” position on the molecule. Multiple synthetic paths have been proposed and investigated, while one final compound was completed and shown to have comparable efficacy with Novartis’s candidate.
Extent: 94 pages
URI: http://arks.princeton.edu/ark:/88435/dsp01dn39x389f
Type of Material: Princeton University Senior Theses
Language: en_US
Appears in Collections:Chemistry, 1926-2023

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