Boronic acid and nitrofuranyl derivatives as potential therapeutics 

Chapter 1 commences with a brief panorama of antibacterial development from the very first modern antibacterial agent, namely Salvarsan® to the very last class of clinically significant antibacterials, namely oxazolidinones. It then goes on to briefly outline the practice of modern Drug Design under the heading ‘Medicinal Chemistry & Drug Discovery’, before discussing molecular targets in bacteria and further reiterating that there are several ‘conserved’ molecular targets in bacteria for which there are no antibacterial agents in clinical use as yet, under the heading ‘Current Antibacterial Targets.’ Whereas in the recent past drug development has often focussed on molecular structures with limited pharmacokinetic parameters e.g. ‘Rule of 5’, there has been extensive research on lead-like compounds other than those in the realm of small molecule drug-likeness. With this borne in mind Chapter 1, Antimicrobial Peptides – a New Chasm, introduces the concept of protein-protein interactions (PPIs), which could pave the way for development of promising therapeutic agents of various properties such as pacidamycin and muraymycin which are all peptide-based antibiotics that are concerned with PPIs. The remainder of Chapter 1 discusses antibacterial resistance and invites the reader to consider other subtle but crucially important facets of antibacterial resistance i.e. Horizontal (Lateral) Gene Transfer & Immunological Tolerance, which are often not considered due to their inherent complexities. Chapter 2 is devoted to a detailed discussion on Solid Phase Synthesis which serves as a gateway to descriptions of Combinatorial Chemistry, and subsequently Dynamic Combinatorial Chemistry (DCC). It is expected that the average reader would like to skip through the literature review of this chapter; however, at the risk of being forward and in the interests of completeness, a knowledge of its existence is thought desirable for the curious reader so that they may wish to utilise them when occasion demands. The aforementioned relatively short introduction in Chapter 2 precedes the detailed preparations of the Dynamic Combinatorial Library of benzodiazaborines and boronate esters herein. Attention is particularly directed to the second half of Chapter 2 in which the Design & Synthesis of novel polyfunctional DCC ligands is thoroughly discussed with a fuller discussion on their DCC systems with 2-formylphenyl boronic acid & formaldehyde which led to identification of novel and intriguing heterocycles. Chapter 2 also features a new reaction for deprotection of the thiazolidine protecting group which is hoped to arm the synthetic chemist with an additional synthetic tool at their disposal. However, a mere perusal of this novel synthetic tool herein by those whose time for chemical synthesis is constrained may assist them to be impressed on the memory. The tortuous path to novel Nitrofuranyl Indole Carboxylate (NInC) hybrids is delineated in Chapter 3 which opens with a brief review of drug conjugates and their linkers, in particular, cleavable linkers so as to precede fuller discussions on the Design, Synthesis & Modification of novel NInC hybrids herein. Considerable detail is given in parts of Chapter 3 which are concerned with the intrinsic colour of nitrofuranyl derivatives; in the author’s opinion, the onus is upon the writer to lay a secure foundation of sound theory of observable phenomena in question for the outsider. Chapter 3 by a large part is confined to ester hydrolysis of carboxyl ester protected NInCs. After numerous failed attempts, the synthesis of a deprotected carboxyl ester NInC was achieved. However, the desired NInC proved unstable and the studies on ester hydrolysis of these novel NInCs suggest that a suitable ester prodrug of these potential drug conjugates may be promising in a clinical setting. Last but not least, it is hoped that a handful of these potentially novel therapeutics could further be developed into leads or drug candidates either in Oxford or elsewhere in an attempt to tackle the ever-increasing antibacterial resistance.

Keywords: Antibiotics/antibacterial, AMR, horizontal/lateral gene transfer, immunological tolerance, dynamic combinatorial chemistry, nitrofurans, indole carboxylate, nitrofuranyl indole carboxylate
Advisor: Schofield, CJ