N-Methyldihydrobenzo[c]phenanthridines Bearing a β-Aminoester Moiety as Potent Antibacterial Agents Against Antibiotic-Resistant Bacteria

The emergence of antibiotic-resistant bacteria is considered a worldwide public health problem for which new antibiotics are needed [1]. Some benzo[c]phenanthridine-type alkaloids have attracted much interest as potential antibacterial agents that target FtsZ and antibiotic efflux proteins [2]. Herein, two natural dihydrobenzo[c]phenanthridines were isolated from the seeds of Bocconia latisepala and then subjected to copper-catalyzed benzylic functionalization to incorporate nitroester, cyanoester, and dialkylmalonic moieties. The in vitro evaluation of 15 semisynthetic compounds against clinical isolates of antibiotic-resistant gram positive (methicillin-resistant Staphylococcus aureus, linezolid-resistant S. epidermidis, vancomycin-resistant Enterococcus faecium, and multidrug-resistant Mycobacterium tuberculosis) and gram negative bacteria (carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae, and OXA-48 and NDM-1-producing K. pneumoniae) allowed us to discover promising antibacterial compounds with minimum inhibitory concentration values ranging from 1.56 to 50 µg/mL. Among bioactives, eight compounds selectively inhibited the growth of the antibiotic-resistant gram positive bacteria at MIC values (1.56 – 6.25 µg/mL) lower than the standard drug levofloxacin (12.5 µg/mL), whereas four derivatives resulted four times less active than levofloxacin against CR A. baumannii.

• References

• 1 Miethke M, Pieroni A. et al. Towards the sustainable discovery and development of new antibiotics. Nature 2021; 5: 726-749
• 2 Li X, Ma S. Advances in the discovery of novel antimicrobials targeting the assembly of bacterial cell division protein FtsZ. Eur J Med Chem 2015; 95: 1-15

Publication History

Article published online:
12 December 2022