Access Type

Open Access Embargo

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

David Crich

Abstract

The ever-growing increase in multidrug resistant infectious diseases is one of the major cause of human mortality, and there is an inherent need for the development of new antibiotics. Since the discovery of streptomycin, AGAs have been playing a very important role in human therapy as highly potent broad-spectrum antibiotics and are listed as one of the critically important antimicrobials by WHO. AGAs act by inhibiting the bacterial protein synthesis and by targeting the A-site present in the small subunit of bacterial ribosome. The clinical use of AGAs is somewhat restricted due to their toxic effects (ototoxicity and nephrotoxicity) and emergence of resistant bacterial strains. However, with the increase in resistance to current antibiotics and significant hurdles in discovering a new class of antibiotics, researchers started to revisit the AGAs, leading to much interest in development of novel AGAs. The goal of this thesis is to utilize the well understood mechanism of action and mechanisms of resistance for the development of novel AGAs. This research work is mainly focused on the modification of neomycin B and paromomycin.

Chapter one introduces the problem of infectious diseases caused by bacteria, history of antibiotics and need for the development of new antibiotics. Then it discusses history of AGAs, their classification, mechanism of action, and toxic effects. It also discusses the common mechanisms of resistance adopted by bacteria and the recent strategies used to evade those resistance mechanisms.

Chapter two discusses a series of modifications made to neomycin B and the influence of each modification on antibacterial activity and ribosomal selectivity. Fourteen different neomycin B derivatives were synthesized and their antiribosomal and antibacterial activities were determined. These derivatives include modifications at 2’-, 4’-, 6’-, and 6’’’ positions. Newly synthesized compounds were also screened against ESKAPE pathogens and engineered strains of E. Coli carrying specific resistance determinants in order to determine their susceptibility to modifications by common AMEs.

Chapter three describes the modifications at 2’- and 5’’- positions in paromomycin and their influence on antiribosomal activity and selectivity. The 2’-position is susceptible to modification by AAC-(2’) and was mainly modified by alkylating the 2’-amino substituent. APH-(3’, 5’’) is one of the most important AME and has been known to modify most of the AGAs. There has been a lot of effort in the past to circumvent the action of this AME and it still remains a great challenge. This chapter also discusses the successful 5’’-formamido and 5’’-ureido modifications to paromomycin. These 5’’-modifications provide an effective alternative for 5’’-hydroxy substituent and are not susceptible to modification at this position by APH-(3’, 5’’).

In Chapter four, an efficient and facile method for the synthesis of highly substituted pyrimidine-2,4-dione derivatives was described. Pyrimidine-2,4-diones are important nitrogen-based heterocycles and present in biologically active natural products and pharmaceuticals. This chapter discuss their synthesis form easily accessible and inexpensive maleic anhydrides and primary amines.

Available for download on Wednesday, August 07, 2019

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