Synthesis and structure-activity-toxicity relationships of DABCO-containing ammonium amphiphiles based on natural isatin scaffold

Abstract

This work deals with the creation of new multifunctional quaternary ammonium compounds (QACs) on natural isatin scaffold as a new generation of antimicrobial agents. 1-R-isatin-3-acylhydrazones containing quaternized DABCO moieties (Dabco-Is-n) with varying hydrophobicity (R = CnH2n+1, where n = 10, 12, 14, 16, 18) were synthesized. The idea was to combine two bactericidal fragments, presumably with different mechanisms of action, in the structure of self-assembling quaternary ammonium compounds. The self-assembly behavior, solubility properties toward hydrophobic dye Sudan I, antimicrobial activity against gram-positive and gram-negative bacteria, fungi, hemolytic activity, cell toxicity (MTT-test) and in vitro anticoagulant and anti-aggregation activities were investigated. Established by tensiometry, conductometry, dynamic light scattering and UV-spectrophotometry, the value of Dabco-Is-n critical micelle concentration is 10 times lower than for Dabco-n surfactants. That is, Dabco-Is-n self-assemblies are responsible factor for the manifestation of antimicrobial activity. Dabco-Is-12 was found to be largely blood biocompatible with low toxicity and low hemolysis (IC50 and HC50 are ≥ 100 µM, negligible coagulation) and with high biological activity against methicillin-resistant strains of S. aureus MRSA-1 and MRSA-2 (MIC = 3.5 and 7.0 µM, respectively) and high solubilization capacity toward hydrophobic dye (Sudan I). Moreover, it forms hydrogen-bonds with drugs (niclosamide and piperine) and displays a good selectivity index toward fungi Candida albicans ATCC 10231. Such new nontoxic Dabco-Is-n biocides with antibacterial and antifungal effects have a good potential for medical applications.