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Synthesis and antibacterial activities of new amidoquinuclidines and their quaternary salts

In recent years, the demand for development of new and more effective antiseptics and disinfectants has risen. One reason for this is the COVID-19 pandemic and the widespread use of these formulations provoking higher incidence of bacterial resistance in future years [1]. Quaternary ammonium compounds (QACs) have been shown to be effective antimicrobial candidates that tend to disrupt the bacterial membrane, leading to leakage of cytoplasm and subsequent cell lysis [2]. We and others have shown that natural products could be used as chemical scaffolds for quaternization to yield QACs of potent antimicrobial activities [3, 4]. Here we report the new series of such natural scaffold- guided structures containing amide bond as a potential substrate for protease degradation. The introduction of amide bond might result in biodegradable QACs, hence variants that have much shorter lifetime in the environment. The 3- aminoquinuclidine was substituted with alkyl chains of different length (10, 12 and 14 C-atoms) to yield precursors for quaternization (Figure 1). The quaternization was performed with appropriate alkyl halide reagents to obtain amidoquinuclidine QACs in good yields (Figure 2). The minimum inhibitory concentrations (MICs) were determined for both, amidoquinuclidines and their QACs, against a panel of Gram-positive and Gram-negative bacteria. As expected, the activity of the QACs was significantly better than for corresponding amidoquinuclidines which is in good correlation with calculated lipophilicity coefficients (cLogP). Our results suggest that amidoquinuclidine QACs could be good antibacterial candidates. The future experiments will elucidate weather these candidates are substrates for protease degradation.

Synthesis, quaternary ammonium compounds, amidoquinuclidines, biological activity, protease degradation

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