Novel Nitro-Heteroaromatic Antimicrobial Agents for the Control and Eradication of Biofilm-Forming Bacteria

Abstract

The synthesis and biological activity of several novel nitrothiazole, nitrobenzothiazole, and nitrofuran containing antimicrobial agents for the eradication of biofilm-forming Gram-negative and Gram-positive pathogens is described. Nitazoxanide (NTZ), nitrofurantoin, and furazolidone are commercial antimicrobials which were used as models to show how structural modification improved activity toward planktonic bacteria via minimum inhibitory concentration (MIC) assays and biofilms via minimum biofilm eradication concentration (MBEC) assays. Structure–activity relationship (SAR) studies illustrate the ways in which improvements have been made to the aforementioned antimicrobial agents. It is of particular interest in this regard that the introduction of a chloro substituent at the 5-position of NTZ (analog 1b) resulted in marked activity enhancement, as did the replacement of the 2-acetoxy substituent in the latter compound with a basic amine group (analog 7b). It is also of importance that analog 4a, which is a simple methacrylamide, displayed noteworthy activity against S. epidermidis biofilms. These lead compounds identified to have high activity towards biofilms provide promise as starting points in future pro-drug studies.

Out of control: The need for standardised solvent approaches and data reporting in antibiofilm assays incorporating dimethyl-sulfoxide (DMSO)

“…Those that did not include relevant DMSO controls ( n = 38 articles) often used low concentrations (≤1% DMSO) to deliver treatments, which likely contributed to a reduced perceived need for a solvent control [ 47 , [51] , [52] , [53] , [54] , [55] ]. Studies that used higher DMSO concentrations without solvent controls were more concerning [ 49 , 50 , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] ] as were studies that did not provide concentrations of DMSO used in treatments and did not include solvent controls [ 43 , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] ]. Media-only control-treated biofilms were frequently used in the calculations [ 50 , 56 , 57 , 78 , 79 ] although it is most appropriate to compare treatments delivered with DMSO to DMSO-only control-treated biofilms normalised to 100% growth as in [ 41 , [80] , [81] , [82] ].…”

N-(Trimethylsilyl)-2-amino-5-nitrothiazole: An Efficient Reagent for the Direct Synthesis of 2-Amino-5-nitrothiazole-Based Antimicrobial Agents

“…In more recent years, ANT-based motifs have found applications in antibiofilm research, showing promising activity against Escherichia coli, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Clostridium difficile. 2 3 4 5 Previously, most of the reported ANT-based amides were prepared via coupling of 2 with acyl chlorides in the presence of auxiliary bases. Standard procedures using ANT with Et 3 N or K 2 CO 3 as bases involve aqueous workups, which are capricious in that emulsions are often encountered, leading to variable yields (vide infra).…”

“…Standard procedures using ANT with Et 3 N or K 2 CO 3 as bases involve aqueous workups, which are capricious in that emulsions are often encountered, leading to variable yields (vide infra). 4 6 Subsequent purifications are also tedious, often requiring cautious column chromatography to obtain purified products. Since ANT derivatives have shown significant medicinal promise, an improved synthetic protocol for their synthesis was required.…”

Editorial for Special Issue “Antibacterial Resistance and Novel Strategies to Eradicate Bacterial Biofilms”

“…Novel nitro-heteroaromatic compounds synthesized by Koenig et al (2021) showed enhanced antimicrobial activity against Staphylococcus epidermidis and Pseudomonas aeruginosa biofilms [ 4 ]. This study modified the structures of commercial antimicrobials Nitazoxanide, nitrofurantoin, and furazolidone.…”

“…Additionally, with analogue 7b (2-Amido-5-chloro-N-(5-nitrothizol-2-yl) benzamide), the 2-acetoxy substituent in 1b was replaced with the primary amine group (analog 7b). Both these analogues (1b and 7b) boosted antibacterial activity in the planktonic and biofilm stages [ 4 ].…”