ABSTRACT
Possible application of incorporating a well-known drug (benzocaine) with cyanoacetamide function to get a powerful synthon ethyl 4-cyanoacetamido benzoate. This synthetic intermediate was used as a precursor for the synthesis of triazine, pyridone, thiazolidinone, thiazole and thiophene scaffolds containing the benzocaine core. Facile coupling, Michael addition, condensation and nucleophilic attack reactions were used to synthesize our targets. The structural features of the synthesized scaffolds were characterized using IR, 1H NMR, 13C NMR and mass spectroscopy. The antibacterial activities against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) were evaluated using ampicillin as a reference drug. DNA/methyl-green colorimetric assay of the DNA-binding compounds was also performed. Theoretical studies of the newly synthesized compounds based on molecular docking and QSAR study were conducted. The molecular docking studies were screened by MOE software for the more potent antibacterial agent 28b and each native ligand against four of S. aureus proteins 1jij, 2xct, 2w9s and 3t07.
Subject(s)
Anti-Bacterial Agents/pharmacology , Benzocaine/chemical synthesis , Benzocaine/pharmacology , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Bacterial Proteins/chemistry , Benzocaine/chemistry , Inhibitory Concentration 50 , Ligands , Microbial Sensitivity Tests , Principal Component Analysis , Staphylococcus aureus/drug effectsABSTRACT
A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.
Subject(s)
Benzocaine/pharmacology , Drug Design , Methemoglobinemia/metabolism , Oxadiazoles/pharmacology , Rodenticides/pharmacology , Animals , Benzocaine/chemical synthesis , Benzocaine/chemistry , Female , Male , Methemoglobin/biosynthesis , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Rats , Rats, Sprague-Dawley , Rats, Wistar , Rodenticides/chemical synthesis , Rodenticides/chemistryABSTRACT
Ethanol was an early anesthetic, and chemists transformed it into better ones. Hypnotic/anesthetic/analgesic molecules prepared from ethanol include barbiturates, benzocaine, chloral hydrate, chloroform, diethyl ether, ethyl chloride, ethylene, etomidate, meperidine, paraldehyde, phenacetin, procaine, tribromoethanol, and urethane. Ethanol was sometimes mixed deliberately with the other anesthetics, and John Snow's inhaled amylene came from the "fusel oil" fraction of rotgut whisky.
