Synthesis and Structure-Activity Relationship of Thioacetamide-Triazoles against Escherichia coli.

Suresh Dharuman,Miranda J Wallace,Richard E Lee,Stephanie M Reeve,Jürgen B Bulitta

doi:10.3390/molecules27051518

Abstract

Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode of action which is dependent on activation by cysteine synthase A. Herein, we report a detailed examination of the anti-E. coli structure–activity relationship of the thioacetamide-triazoles. Analogs of the initial hit compounds were synthesized to study the contribution of the aryl, thioacetamide, and triazole sections. A clear structure–activity relationship was observed generating compounds with excellent inhibition values. Substitutions to the aryl ring were generally best tolerated, including the introduction of thiazole and pyridine heteroaryl systems. Substitutions to the central thioacetamide linker section were more nuanced; the introduction of a methyl branch to the thioacetamide linker substantially decreased antibacterial activity, but the isomeric propionamide and N-benzamide systems retained activity. Changes to the triazole portion of the molecule dramatically decreased the antibacterial activity, further indicating that 1,2,3-triazole is critical for potency. From these studies, we have identified new lead compounds with desirable in-vitro ADME properties and in-vivo pharmacokinetic properties.

Highlights

The usage of antibiotics to treat and prevent bacterial infections has saved millions of people since their introduction
Gram-negative bacteria, in this study we explore identifying novel compounds for Gram-negative bacteria, in this study we explore the the structure–activity relationships of with to potent lead in this study we explore the structure–activity relationships ofgoal the Thioacetamide triazoles (TATs)
TAT series, series, we we proposed proposed aa stepwise study to evaluate the contributions of the functional motifs found within the a stepwise stepwise study study to to evaluate evaluate the the contributions contributions of of the the functional functional motifs motifs found found within within the the scaffold

Summary

Introduction

The usage of antibiotics to treat and prevent bacterial infections has saved millions of people since their introduction. Antimicrobial resistance significantly increases the morbidity and mortality associated with bacterial infections in humans [2]. One reason for such a high mortality rate is the lack of alternative antibiotics to treat drug-resistant pathogens [3]. We have identified a thioacetamidetriazole hit series via a metabolically biased high-throughput screen against E. coli K12 in a search for novel antifolates (Figure 1) [5]. We demonstrated that these compounds function as prodrugs and are activated by the cysteine synthase A (CysK) enzyme. Thioacetamide triazoles (TATs) form a false product with the CysK substrate O-acetyl-L-serine [7] and inhibit the growth of E. coli

Methods

Results

Conclusion