title: Synthesis and structure-activity relationship of novel 1,4-diazabicyclo[2.2.2]octane derivatives as potent antimicrobial agents.
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.
authors: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090 Novosibirsk, Russian Federation; Institute of Molecular and Cellular Biology SB RAS, 8/2 Lavrentiev Avenue, 630090 Novosibirsk, Russian Federation; Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russian Federation. Electronic address: yarinich-1@yandex.ru.
authors: Lyubov A
authors: LA
authors: Yarinich
authors: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090 Novosibirsk, Russian Federation.
authors: Ekaterina A
authors: EA
authors: Burakova
authors: Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russian Federation; Institute of Solid State Chemistry and Mechanochemistry SB RAS, 18 Kutateladze St., 630128 Novosibirsk, Russian Federation.
authors: Boris A
authors: BA
authors: Zakharov
authors: Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russian Federation; Institute of Solid State Chemistry and Mechanochemistry SB RAS, 18 Kutateladze St., 630128 Novosibirsk, Russian Federation.
authors: Elena V
authors: EV
authors: Boldyreva
authors: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090 Novosibirsk, Russian Federation.
authors: Irina N
authors: IN
authors: Babkina
authors: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090 Novosibirsk, Russian Federation.
authors: Nina V
authors: NV
authors: Tikunova
authors: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentiev Avenue, 630090 Novosibirsk, Russian Federation.
authors: Vladimir N
authors: VN
authors: Silnikov
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009795:Octanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001643:Bridged Bicyclo Compounds; D009795:Octanes; C026728:octane
keywords: Antimicrobial activity; DABCO derivatives; QAC; Time-kill efficacy; X-ray diffraction