Date

2019

Department or Program

Chemistry

Primary Wellesley Thesis Advisor

Michael J Hearn

Abstract

Tuberculosis (TB) is an infectious disease caused by the organism Mycobacterium tuberculosis (MTB). Improved sanitation and successful chemotherapy have largely eliminated TB in industrialized countries, but it remains a serious threat to lower socio-economic classes, the immunocompromised population, and developing countries where industrialization is just taking hold. Although two new drugs have surfaced in the last decade, they are largely reserved for compassionate cases because of the severity of their side effects. The first-line TB treatment prescribed by the World Health Organization and the Center for Disease Control and Prevention remains the comparatively small number of drugs synthesized or isolated in the 1950’s and 1960’s. These drugs, while currently effective, can cause adverse side effects such as liver toxicity. Additionally, the emergence of strains of drug-resistant TB threatens to completely undermine existing treatment regimens and enable TB to reach a level of prevalence not experienced for the past century.

In the past decade, studies have suggested intriguing antitubercular possibilities offered by applying modern methods to a very early class of drugs: the sulfa drugs. Sulfa drugs work by mimicking the natural molecule para-aminobenzoic acid, inhibiting dihydropteroate synthase (DHPS) and resulting in cell death. Arylamine N-acetyltransferases (NATs) de-activate sulfa drugs inside the body by catalyzing the transfer of an acetyl group onto position N4 of the sulfa molecule. NATs also appear in M. tuberculosis, where they act as a defense mechanism for MTB against chemotherapy.

My work in the Hearn lab has been guided by recent crystallographic images of the DHPS binding pocket and the deactivating mechanism of NATs, as well as by previous studies in our lab that demonstrated that acylation can improve activity and bioavailability while reducing toxicity. Our work began with the development of a reliable protocol to prepare the acetylated NAT metabolites. We then explored a number of different procedures for increasing acyl chain length at N4, focusing on derivatives of sulfamethazine; and then continued to selective di-acylation at both N4 and N1, varying both chain length and steric bulk for a number of different sulfa drug scaffolds. Several of our acylated sulfa derivatives possess improved biological and anti-tubercular properties over their parent drugs. Moreover, the compounds serve as probes of the structural factors influencing biological activity such as fit within DHPS, resistance to the de-activating effects of NATs, and permeability.

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