The emergence of drug-resistant bacteria leading to difficult-to-control infections is a major threat to human life and has become one of the leading causes of death [1,2]. Many mechanisms contribute to the development of antibacterial resistance, one of which is the formation of biofilm [3]. Biofilm is a microbial community attached to biotic or abiotic surfaces, which can cause bacterial drug resistance by blocking the infiltration of antibiotics, inducing bacterial dormancy, and promoting other resistance mechanisms [[4], [5], [6]]. Currently, the main clinical treatment for biofilm is local continuous administration, which may lead to unpredictable adverse reactions [7]. Approved drugs for treating biofilms, such as daptomycin and telavancin, still have issues like nephrotoxicity [8]. Therefore, there is an urgent need to develop safe antibacterial agents against biofilm formation.

Halogenated pyrroles are frequently found to possess antibiofilm activity [9]. Among them, polyhalogenated 2-hydroxyphenyl(1H-pyrrol-2-yl) methanones, known as pyrrolomycins, derived from fermentation broth of Actinosporangium and Streptomyces species, exhibit both potent Staphylococcus biofilm inhibition activity and strong activity against Gram-positive bacteria [10,11]. Studies have shown that the antibacterial activity of these compounds may be attributed to the presence of amino and phenolic hydroxyl groups, which can act as proton carriers, while their antibiofilm activity is more dependent on the lipophilicity brought by high degrees of halogenation [11,12]. Currently, most effective pyrrolomycin analogues have been synthesized mainly by replacing the substituents on the pyrrole ring (Fig. 1) [[12], [13], [14]]. Unfortunately, the oral toxicity of these compounds limits their clinical application [8].

As a dominant pharmacophore, thiazole exists widely in the structure of antibacterial drugs [15]. In terms of antibiofilm activity, some thiazole compounds have shown inhibitory activity against either Gram-positive or Gram-negative bacterial biofilm (Fig. 2) [[16], [17], [18], [19], [20]]. However, most of these compounds lack inhibitory effects on bacterial growth themselves and need to be used in combination with other antibacterial drugs. In the aspect of drug modification, as a weakly alkaline electron-rich aromatic ring, the introduction of thiazole groups may not only enhance the efficacy by providing a variety of non-covalent bond interactions but also avoid drug resistance or reduce toxicity by changing the physical properties of drugs [21].

Halogenated pyrroles with excellent antibacterial and antibiofilm activity have attracted our research interest, while addressing their toxic and side effects has also been our concern. We speculate that the pharmacophores of these compounds may be halogenated pyrrole and phenol, which could potentially act as proton carriers, with their activity being influenced by both proton carrier activity and lipophilicity, where proton carrier activity is related to their toxicity [11,12]. Therefore, we attempted to use thiazole to connect these two active groups. For one thing, increasing the compound's pKa to reduce its toxic and side effects, and for another, further enhancing the compound's lipophilicity to maintain its activity [22,23]. In addition, we have previously attempted to replace halogenated pyrrole with substituted pyrazole and obtained antimicrobial agents with good antibiofilm activity [8], also inspired by previous work [24], we synthesized some pyrazole structures to investigate their activity. This paper described the chemical synthesis, biological evaluation, and structure-activity relationships of these pyrrole or pyrazole derivatives.