Many antibacterial drugs are ineffective because of excessive and inappropriate use of antibacterial agents, which leads to bacterial resistance. A number of new bacterial topoisomerase inhibitors from the new promising classes – NBTIs (novel bacterial topoisomerase inhibitors) have already been discovered. However, the compounds discovered so far have excellent antibacterial efficacy, but a suboptimal safety profile. Their main weakness is the inhibition of hERG (the human ether-a-go-go-related gene) potassium channels, resulting in cardiotoxicity. Consequently, there are no active substances from this class on the market so far. While designing the NBTI syntheses, we focused on the optimization of the spacer and the right-hand part (RHS) while maintaining the well-known left-hand part (LHS) of the molecule. The final compounds were analysed by NMR, HRMS, and IR spectroscopy. Additionally, we determined their melting point temperature. Furthermore, we performed biological testing and determined the compounds' half-maximal inhibitory concentration (IC50), minimal inhibitory concentration (MIC), and hERG block potency. Firstly, we started with RHS optimization. The goal was to research how the type of aromatic ring and attached substituents affect the antibacterial activity. Since the most potent inhibitory effect among all synthesized final compounds was achieved by the compound with phenyl-halogenated RHS, we concluded that halogen interactions are not easily replaceable. Bioisosteric replacement of halogens with a methyl group or with an additional phenyl ring leads to weaker but still very strong inhibitory effect and antibacterial activity on Gram-positive bacteria. Therefore, the influence of van der Waals bonds is by no means negligible. We also concluded that the proper orientation of the molecule is a necessity for appropriate functioning. Moreover, we discovered that thiophene is not the most suitable right-hand side of the molecule. Secondly, we synthesized a series of NBTI analogues with cyclohexane or tetrahydropyran instead of a piperidine spacer. To improve safety, we wanted to remove the tertiary amine, which is known to have a fairly high impact on hERG. These structural changes led us to excellent inhibitory and antibacterial activity and at the same time, they reduced the inhibitory activity on hERG channels. Additionally, we have discovered a new breakthrough compound with, by far, the best ratio between strong antibacterial activity and an improved safety profile in this series of compounds, which contains an amide bond instead of methylene amine and shows great potential in the fight against bacterial resistance against Gram-positive bacteria.
|
