SF₅- and SCF₃-substituted tetrahydroquinoline compounds as potent bactericidal agents against multidrug-resistant...

Bacteria persister cells are immune to most antibiotics and hence compounds that are active against persister bacteria are needed. We screened a chemical library of SF₅- and SCF₃-substituted tetrahydroquinoline compounds, synthesized via the Povarov reaction, for antibacterial activity and identified active compounds that displayed good activities against many Gram-positive bacteria, including persisters. The most potent of these compounds, HSD1835, inhibited the growth of drug-resistant Gram-positive bacterial pathogens (including clinical strains) at concentrations ranging from 1 μg mL^-1 to 4 μg mL^-1. Several of the SCF₃- and SF₅-containing compounds were active against methicillin-resistant Staphylococcus aureus (MRSA) and against the two most fatal strains of vancomycin-resistant Enterococcus (VRE), VRE faecalis and VRE faecium. The compounds showed bactericidal activity against stationary phase persister MRSA in time-kill assays. Mechanistic studies showed that HSD1835 acts by disrupting bacterial membranes. Scanning electron microscopy (SEM) was used to confirm bacterial membrane disruption. Interestingly, in a 30 day serial exposure experiment, MRSA remained susceptible to low-dose HSD1835 whilst resistance to ciprofloxacin and mupirocin emerged by day 10. Analogs of HSD1835, which did not bear the SF₅ or SCF₃ moieties, were inactive against bacteria. Recent reports (G. A. Naclerio, N. S. Abutaleb, K. I. Onyedibe, M. N. Seleem and H. O. Sintim, RSC Med. Chem. 2020, 11, 102-110 and G. A. Naclerio, N. S. Abutaleb, D. Li, M. N. Seleem and H. O. Sintim, J. Med. Chem. 2020, 63(20), 11934-11944) also demonstrated that adding the SF₅ or SCF₃ groups to a different scaffold (oxadiazoles) enhanced the antibacterial properties of the compounds, so it appears that these groups are privileged moieties that enhance the antimicrobial activities of compounds.