Design, green one-pot synthesis and molecular docking study of novel N,N-bis(cyanoacetyl)hydrazines and bis-coumarins as effective inhibitors of DNA gyrase and topoisomerase IV

• Published in: Bioorganic chemistry 2020-04, Vol.97, p.103672, Article 103672
• Main Authors: Metwally, Nadia Hanafy, Abdallah, Sanaa Osman, Mohsen, Marwa Maher Abdel
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Bacteria - drug effects; Bacteria - enzymology; Bacterial Infections - drug therapy; Bacterial Infections - microbiology; Bis-coumarins; Combinatorial Chemistry Techniques; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; DNA Gyrase - metabolism; DNA gyrase and topoisomerase IV; DNA Topoisomerase IV - antagonists & inhibitors; DNA Topoisomerase IV - metabolism; Drug Design; Enzyme inhibition; Escherichia coli - drug effects; Escherichia coli - enzymology; Green Chemistry Technology; Humans; Hydrazines - chemical synthesis; Hydrazines - chemistry; Hydrazines - pharmacology; Molecular Docking Simulation; Molecular docking study; N,N-bis(cyanoacetyl)hydrazines; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Streptococcus mutans - drug effects; Streptococcus mutans - enzymology; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Topoisomerase Inhibitors - chemical synthesis; Topoisomerase Inhibitors - chemistry; Topoisomerase Inhibitors - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103672

[Display omitted] •A series of N,N-bis(cyanoacetyl)hydrazines and bis-coumarins designed and synthesized.•Compound 15a is the most toxic compound against Escherichia coli compared to gentamicin.•DNA gyrase and topoisomerase IV assay was performed for N,N-cyanohydrazides and bis-coumarins.•Compound 15a exhibited high potency against DNA gyrase and topoisomerase IV. A novel, quick, environmentally safe, and one-pot synthesis of a series of N,N-bis(cyanoacetyl)hydrazine derivatives, bis-imino-2H-chromenes and bis-2-oxo-2H-chromene derivatives have been designed. Some selected newly synthesized compounds were investigated in vitro for their antibacterial activity. Compound 5j is the most toxic compound against Staphylococcus aureus with activity index 171%, followed by compound 15b with activity index 136% compared to standard drug ampicillin. Moreover, compound 15a is the most toxic compound against Escherichia coli with activity index 111% compared to standard drug gentamicin. Minimum inhibitory concentration (MIC) was carried out for compounds with high antibacterial activity. Compound 5j has good MIC (7.8 μg/ml) against Staphylococcus aureus while 15a has good MIC (31.25 μg/ml) against Streptococcus mutans which is better than MIC of the standard drug ampicillin (MIC = 62.5 μg/ml). Compounds 5j, 5k, 15a, 15b and 15e which have good MIC values were introduced to enzyme assay against DNA gyrase and topoisomerase IV. The results showed that compound 15a can strongly inhibit DNA gyrase and topoisomerase IV (IC50 = 27.30 and 25.52 μM respectively), compared to methotrexate as the standard drug (IC50 = 29.01 and 23.55 μM respectively). Structure-activity relationships were also discussed based on the biological and docking simulation results.