Synthesis and Antibacterial Evaluation of Bis‐thiazolium, Bis‐imidazolium, and Bis‐triazolium Derivatives

Abstract

Given the worldwide spreado fb acterial drug resistance, there is an urgent need to develop new compounds that exhibit potent antibacterial activity and that are unimpaired by this phenomenon. Quaternary ammonium compounds have been used for many years as disinfectants, but recent advances have shown that polycationic derivatives exhibit much stronger activity and are less prone to bacterial resistance than commonly used monocationic compounds.I nt his sense, we prepared three series of new bis-cationic compounds:b is-thiazoliums, bis-imidazoliums,a nd bis-1,2,4-triazoliums. If some compounds of the first series showedf air antibacterial activity, most of those belongingt ot he two other series were highly potent, with minimum inhibitory concentrationsc loset o1 mgmL À1 . Some of them also exhibited low toxicityt owarde ukaryotic MRC-5 lung fibroblasts, and we showedt hat this toxicityi s clearly correlated with clogP. Finally,f our selected compounds were found to exhibit aclear bactericidal effect.The World Health Organizationr ecently published al ist [1] of 12 bacteria whose capacity for resistance against antibiotics is so high that they constitute ar eal threat to human health;t his highlightst hat the time to act is now.Arecent review chaired by Jim O'Neill [2] also listed major recommendations to fight antimicrobial resistance. These include improving hygiene, minimizing the unnecessaryu se of antibiotics, improving global surveillance of drug resistance, and implementing better incentives to promote investment for new drugs.D eveloping new chemicale ntitiesi st hus urgently required. Quaternary ammonium compounds (QACs) were first discovered by Domagk in 1935 [3] and were used for many years as skin disinfectants. Mono-ammonium compounds such as benzalkonium chloride or cetylpyridinium chloride were followed by bis-ammonium compounds such as dequalinium chloride and chlorhexidine.

Quaternary Ammonium Compounds (QACs) and Ionic Liquids (ILs) as Biocides: From Simple Antiseptics to Tunable Antimicrobials

“…Thomas and colleagues synthesized QACs based on bis-thiazole 67, bis-imidazole 68 and bis-triazole 69. While thiazole derivatives with an alkyl spacer and without lipophilic tails 67 did not show high activity, bis-QACs with nitrogen heterocycles 68-69 demonstrated MIC values lower than that of CHG [113].…”

Ammonium‐Charged Sterically Hindered Phenols with Antioxidant and Selective Anti‐Gram‐Positive Bacterial Activity

“…The presence of a phenolic hydroxy and a hydrazone moiety in the structure of these compounds may also cause them to exhibit antioxidant properties . On the other hand, it is known that quaternary ammonium salts have pronounced antimicrobial properties due to the ability to bind to the negatively charged surface of the bacterial cell membrane . In our opinion, the combination of a phenolic substituent, a hydrazone moiety and an ammonium center in one molecule will solve the problem of the solubility of the target compounds in water along with high antioxidant and antimicrobial activities.…”

Functionalized Cyclopentenones and an Oxime Ether as Antimicrobial Agents

“… [5] Moreover the appearance of vancomycin intermediate S. aureus (VISA) and vancomycin‐resistant S. aureus (VRSA) is a cause of concern. [6] For this reason the search for new molecules with antibiotic properties, especially against MRSA[ 7 , 8 , 9 ] is urgently needed. Concerning antimicrobial naturally occurring products, examples such as Nigrosporione A–B [10] and Palmenone A–B [11] contains a cyclopentenone (CP) scaffold (Scheme 1 A).…”