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Quinuclidine and its derivatives - compounds of high biological and medicinal potential

Quaternary ammonium compounds (QACs) have long been praised for their powerful antimicrobial potential. With a wide range of application, from different industries to pharmacy and medicine, these compounds are omnipresent ingredients of many commercial products. However, recent studies show that as much as 83% of MRSA isolates are resistant toward most of the commonly used QACs. Therefore, elucidation of resistance mechanism(s) and development of new potent QACs are in the centre of further research in the field. Quinuclidine is a bicyclic part of alkaloids isolated from a bark of the Cinchona trees. Even though these alkaloids have long been used in a traditional medicine, the biological potential of quinuclidine derivatives is still underexplored. Apart from its anticholinergic, antiparasitic, antioxidative and antitumor activity, some quinuclidine derivatives have been shown to act on FitZ protein, known to be essential for bacterial cell division. All this motivated us to synthesize new quinuclidine containing QACs in order to further explore its antimicrobial potential and to develop new and powerful naturally derived QACs. Our studies have shown that quaternisation of substituted quinuclidine improves its antimicrobial activity by several hundred folds and that this activity depends on the type of substituent used for quaternisation. Aryl- quinuclidines typically had lower antimicrobial activity than their alkyl counterparts. Also, somewhat better antimicrobial activity was observed toward Gram-positive bacteria, suggesting that bacterial membrane might be involved in the mode of action mechanism. Therefore, the PI- uptake measurements were performed along with atomic force microscopy (AFM) and indeed, obtained results indicated bacterial membrane perforation. Moreover, alkyl-quinuclidines, more specifically an identified candidate with the longest alkyl chain, exhibited the best antimicrobial activity with the lowest MIC values across selected panel of the bacteria and good activity toward S. aureus biofilms. In addition, this compound had lower toxicity toward healthy human cell lines than the referent QACs, suggesting that quinuclidine could serve as a new possible core molecule for future QACs development.

quaternary ammonium compounds, quinuclidine, antimicrobials, bioactivity

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