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Synthesis and structure-activity relationship of novel 1,4-diazabicyclo[2.2.2]octane derivatives as potent antimicrobial agents.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2015 May 05; Vol. 95, pp. 563-73. Date of Electronic Publication: 2015 Mar 17. - Publication Year :
- 2015
-
Abstract
- A series of new quaternary 1,4-diazabicyclo[2.2.2]octane derivatives was synthesized and evaluated for activity against several strains of both Gram positive and Gram negative bacteria and one strain of fungus under different inoculum size. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against six species of microorganisms were tested. Results show a clear structure-activity relationship between alkyl chain length of substitutions of 1,4-diazabicyclo[2.2.2]octane tertiary amine sites and antimicrobial activity. In the case of compounds 4a-4k, MIC was found to decrease with the increase of the alkyl chain length from ethyl to dodecyl and then to increase at higher chain length (n > 14). The MIC values were found to be low for the compounds 4f and 4g with alkyl chains ranging from 10 to 12 carbons in length (1.6 μg/ml) and were comparable to the reference drug Ciprofloxacin. Also, time-kill assay was performed to examine the bactericidal kinetics. Results indicated that 4f and 4g had rapid killing effects against Staphylococcus aureus, and eliminated 100% of the initial inoculum of bacteria in 2.5 h at the concentration of 10 μg/ml. In addition, compound 4g eliminate more than 99.9% of the initial inoculum of Ps. aeruginosa after 2.5 h of interaction but the activity of compound 4f against this species seems to be weak. Thus, 4g had strong bactericidal activity and could rapidly kill Gram positive S. aureus, as well as Gram negative Ps. aeruginosa at low and high inoculum size.<br /> (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Anti-Bacterial Agents chemistry
Anti-Bacterial Agents toxicity
Cell Line
Chemistry Techniques, Synthetic
Humans
Kinetics
Mice
Microbial Sensitivity Tests
Models, Molecular
Molecular Conformation
Octanes chemistry
Octanes toxicity
Pseudomonas aeruginosa drug effects
Staphylococcus aureus drug effects
Structure-Activity Relationship
Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents pharmacology
Bridged Bicyclo Compounds chemistry
Octanes chemical synthesis
Octanes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 95
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25867737
- Full Text :
- https://doi.org/10.1016/j.ejmech.2015.03.033