Synthesis and Structure-Activity Relationship of Novel 1,4-Diazabicyclo[2.2.2]octane Derivatives as Potent Antimicrobial Agents Full article
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European Journal of Medicinal Chemistry
ISSN: 0223-5234 , E-ISSN: 1768-3254 |
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| Output data | Year: 2015, Volume: 95, Pages: 563-573 Pages count : 11 DOI: 10.1016/j.ejmech.2015.03.033 | ||||||||
| Tags | Antimicrobial activity, DABCO derivatives, QAC, Time-kill efficacy, X-ray diffraction | ||||||||
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| Affiliations |
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Funding (1)
| 1 | Council for Grants of the President of the Russian Federation | НШ-221.2012.3 |
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.
Cite:
Yarinich L.A.
, Burakova E.A.
, Zakharov B.A.
, Boldyreva E.V.
, Babkina I.N.
, Tikunova N.V.
, Silnikov V.N.
Synthesis and Structure-Activity Relationship of Novel 1,4-Diazabicyclo[2.2.2]octane Derivatives as Potent Antimicrobial Agents
European Journal of Medicinal Chemistry. 2015. V.95. P.563-573. DOI: 10.1016/j.ejmech.2015.03.033 WOS Scopus РИНЦ ANCAN OpenAlex
Synthesis and Structure-Activity Relationship of Novel 1,4-Diazabicyclo[2.2.2]octane Derivatives as Potent Antimicrobial Agents
European Journal of Medicinal Chemistry. 2015. V.95. P.563-573. DOI: 10.1016/j.ejmech.2015.03.033 WOS Scopus РИНЦ ANCAN OpenAlex
Dates:
| Submitted: | Sep 30, 2014 |
| Accepted: | Mar 17, 2015 |
| Published online: | Mar 17, 2015 |
| Published print: | May 1, 2015 |
Identifiers:
| Web of science: | WOS:000354139900048 |
| Scopus: | 2-s2.0-84929268319 |
| Elibrary: | 24031828 |
| Chemical Abstracts: | 2015:468762 |
| Chemical Abstracts (print): | 162:603823 |
| OpenAlex: | W2031056395 |