Design, synthesis, analgesic, antibacterial and docking studies of novel 8-piperazinylcaffeine carboxylate ionic liquids

Abstract

This paper presents a comprehensive evaluation of novel 8-piperazinylcaffeine carboxylate ionic liquids, including their design, synthesis, characterization, analgesic and antibacterial properties, as well as docking studies. These unique salts were produced by combining 8-piperazinyl caffeine (8-PC) with various carboxylic acids, some of which are commonly used nonsteroidal anti-inflammatory drugs (NSAIDs). Through in vivo experiments on female mice using the formalin test, the analgesic efficacy of different 8-PC salts with various NSAIDs was assessed. Results demonstrated that a majority of these salts exhibited significant analgesic activity when compared to NaIBP, a standard reference drug. Particularly noteworthy was the enhanced analgesic effect of the 8-PC's NSAIDs salts (11a, 11c–e, and 11k) compared to their corresponding sodium salts, which was attributed to the presence of the 8-PC cation (synergistic effect). Furthermore, all synthesized salts were subjected to in vitro testing against Gram-positive Staphylococcus aureus (PTCC 1133), Gram-negative Pseudomonas aeruginosa (ATCC 27853), and Escherichia coli (PTCC 1330) bacteria. Among them, salt 11k displayed notable antibacterial activity, especially against P. aeruginosa, a dangerous opportunistic pathogen. Additionally, docking analysis revealed strong binding of the synthesized 8-PC and NSAID salts to the active site of the COX-2 enzyme.