Investigation of quinolone‐tethered aminoguanidine as novel antibacterial agents. Issue 10 (8th June 2022)

• Record Type: Journal Article
• Authors: Angula, Klaudia T.; Legoabe, Lesetja J.; Jordaan, Audrey; Warner, Digby F.; Beteck, Richard M.
• Is Part Of: Archiv der Pharmazie. Volume 355:Issue 10(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-08
• Subjects: tuberculosis -- ESKAPE pathogens -- aminoguanidine -- quinolones -- thiosemicarzone; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202200172
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: A recent study identified quinolone‐based thiosemicarbazone with an MIC90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone‐tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC90 values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating >50% growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non‐pan‐assay interfering compound. Abstract : Further optimization of quinolone‐based thiosemicarbazone was performed, leading to quinolone‐tethered aminoguanidine molecules with good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series (MIC90 = 0.49/0.90 µM and 0.49/0.60 µM, respectively). In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes and to be a non‐pan‐assay interfering compound.