| Резюме: | <p>The research described in this thesis concerns the development of novel small molecule inhibitors of biologically relevant nucleophilic hydrolases, i.e. β-lactamases, SARS-CoV-2 main protease (Mpro) and elastases, which are therapeutic targets for combatting public health threats associated with antimicrobial resistance, the COVID-19 pandemic and chronic inflammatory diseases, respectively. The work focused on the synthesis and structure activity relationship (SAR) exploration of two small molecule templates, i.e. C6-functionalised benzoxaboroles and thiophene-fused γ-lactams. These templates have potential to inhibit nucleophilic enzymes by covalent reaction with nucleophilic active site residues, owing to the presence of their electrophilic boron or γ-lactam carbonyl groups, respectively.</p>
<p><strong>Chapter 2</strong> describes the synthesis of a set of C6-functionalised benzoxaborole derivatives and their biochemical investigation as inhibitors of clinically relevant serine β-lactamases (SBLs) and metallo β-lactamases (MBLs). The results reveal C6-sulfonamide-substituted benzoxaboroles as promising SBL and MBL inhibitors, subject to further optimisation. <strong>Chapter 3</strong> describes studies evaluating the potential of the thiophene-fused γ-lactam scaffold for covalent inhibition of SARS- CoV-2 Mpro. A set of α- and N-substituted γ-lactams was synthesised; subsequent SAR and mass spectrometry studies indicate that thiophene-fused γ-lactams can effectively inhibit Mpro <em>via</em> reversible covalent reaction with the nucleophilic Cys145. <strong>Chapter 4</strong> extends inhibition studies of thiophene-fused γ-lactam and benzoxaborole derivatives to SAR studies on porcine pancreatic elastase (PPE) and human neutrophil elastase (HNE). The results lay groundwork for the development of benzoxaborole-based compounds as elastase inhibitors. The PPE inhibitory activity of both thiophene-fused γ-lactams and C6-functionalised benzoxaboroles is further supported by mass spectrometry and crystallographic studies which provide insights into their mechanisms of inhibition involving covalent reaction with the nucleophilic Ser195.</p>
<p>Overall, the work presented in this thesis identifies benzoxaboroles and thiophene-fused γ-lactam compounds as promising templates for development of potent covalently reacting small molecule inhibitors of biologically important nucleophilic hydrolases.</p>
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