chiniofon and nitroxoline

Two substituted oxines, nitroxoline (5) and 5-chloroquinolin-8-yl phenylcarbamate (22), were identified as hits in a high-throughput screen aimed at finding new anti-angiogenic agents. In a previous study, we have elucidated the molecular mechanism of antiproliferative activity of nitroxoline in endothelial cells, which comprises of a dual inhibition of type 2 human methionine aminopeptidase (MetAP2) and sirtuin 1 (SIRT1). Structure-activity relationship study (SAR) of nitroxoline offered many surprises where minor modifications yielded oxine derivatives with increased potency against human umbilical vein endothelial cells (HUVEC), but with entirely different as yet unknown mechanisms. For example, 5-nitrosoquinolin-8-ol (33) inhibited HUVEC growth with sub-micromolar IC(50), but did not affect MetAP2 or MetAP1, and it only showed weak inhibition against SIRT1. Other sub-micromolar inhibitors were derivatives of 5-aminoquinolin-8-ol (34) and 8-sulfonamidoquinoline (32). A sulfamate derivative of nitroxoline (48) was found to be more potent than nitroxoline with the retention of activities against MetAP2 and SIRT1. The bioactivity of the second hit, micromolar HUVEC and MetAP2 inhibitor carbamate 22 was improved further with an SAR study culminating in carbamate 24 which is a nanomolar inhibitor of HUVEC and MetAP2.

Topics: Aminopeptidases; Angiogenesis Inhibitors; Cell Proliferation; Cell Survival; Enzyme Inhibitors; Glycoproteins; High-Throughput Screening Assays; Human Umbilical Vein Endothelial Cells; Humans; Hydroxyquinolines; Methionyl Aminopeptidases; Nitroquinolines; Phenylcarbamates; Sirtuin 1; Structure-Activity Relationship

In vitro studies on the antibacterial activity of nitroxoline and sulphamethizole, alone and in combination, were undertaken and minimal inhibitory concentrations (MICs) determined on a range of urinary pathogens. Eighty per cent of the strains tested were sensitive to less than or equal to 16 mg/l of nitroxoline, and all strains, including Pseudomonas aeruginosa and Streptococcus faecalis, were sensitive to less than or equal to 64 mg/l of nitroxoline. No synergism could be demonstrated with sulphamethizole, but the combination was antagonistic when tested against strains of Ps. aeruginosa and Strep. faecalis. An in vivo study on 10 volunteers showed excellent urinary levels of nitroxoline and sulphamethizole after an oral dose of 160 mg of each agent, and 6-hour urinary nitroxoline levels were greater than or equal to 64 mg/l in 9 of the 10 subjects, and sulphamethizole levels were greater than or equal to 64 mg/l in all 10 subjects. Laboratory findings suggest that nitroxoline and sulphamethizole are both suitable agents for use in urinary tract infections caused by organisms sensitive to these agents, but there appears to be litte advantage in using them in combination.

Topics: Drug Combinations; Enterococcus faecalis; Escherichia coli; Humans; Hydroxyquinolines; Nitro Compounds; Nitroquinolines; Oxyquinoline; Sulfamethizole; Sulfathiazoles; Urinary Tract Infections

Topics: Adult; Anemia, Hemolytic; Female; Glucosephosphate Dehydrogenase Deficiency; Humans; Hydroxyquinolines; Nitro Compounds; Nitroquinolines; Oxyquinoline