Synthesis And Anti-bacterial Activity Of α-C Alkyl Homologues Of Octanoyl Acetal

Based on the structure of octanoyl acetal, threeα-C alkyl homologues of octanoyl acetal sodium sulfite (HOU-C₈C_n) including 2-octanoyl-1-hydroxy propyl sulfonate (HOU-C₈C₁),2-octanoyl-1-hydroxy butyl sulfonate (HOU-C₈C₂),2-octanoyl-1-hydroxy hexyl sulfonate (HOU-C₈C₄) had been synthesized successfully in our laboratory by modification theα-C of HOU-C₈. Their anti-bacterial activity in vitro were studied with their lipophilicity and charge density.Octanoyl acetal possesses two methylene groups. One of them isα- methylene, which effeeted by two carbonyl groups become active methylene. Soα-H is the strongest active hydrogen atom. Hence when octanoyl avetal reacted with halogenated hydrocarbon under alkali in organic solution, alkylation occured onα-C is easiest. Based on above principle,α-H of octanoyl acetal was substituted by methyl, ethyl and butyl respectively to yield threeα-C alkyl homologues of octanoyl acetal sodium sulfite (HOU-C₈C_n), viz., 2-octanoyl-1-hydroxy propyl sulfonate (HOU-C₈C₁), 2-octanoyl-1-hydroxy butyl sulfonate (HOU-C₈C₂) and 2-octanoyl-1-hydroxy hexyl sulfonate (HOU-C₈C₄).The purity and the mother group of three homologucs were determined by melting point test, thin layer chromatography and UV chromatogram analysis; double linkage and hydroxy in the molecules were determined by UV chromatogram analysis; carboxyl group was determined by sodium bisulfite addition test and uchsine-aldehyde test; CH₃,-CH₂,-OH and -C=O were determined by infra-red spectrum; the binds among atoms were determined by ¹HNMR,¹³CNMR and MS. In all, the molecular structures of threeα-C alkyl homologues of octanoyl acetal sodium sulfite were conformed.The anti-bacterial activities varied with the number of carbon atoms inα-C site and lipophilicity of the three homologues. The anti-bacterial activities for S. aureus of HOU-C_n and HOU-C₈C_n at different concentrations were tested by tube broth dilution method.The results indicated that the minimal inhibitory concentration (M/C) of HOU-C₈,HOU-C₁₀, HOU-C₁₂, HOU-C₈C₁,HOU-C₈C₂ and HOU-C₈C₄ for S. aureus were: 62.5μg/ml, 62.5μg/ml, 31.25μg/ml, 250μg/ml, 184.2μg/ml and 62.5μg/ml and the minimum bactericidal concentration (MBC) were: 62.5μg/ml, 31.25μg/ml, 31.25μg/ml, 250μg/ml, 184.2μg/ml and 62.5μg/ml.HOU-C₈ is the mother mode of HOU-C₈C_n, the anti-bacterial activity for S. aureus was stronger than HOU-C₈C_n. Obviously, afterα-H of octanoyl acetal was substituted by alkyl, their anti-bacterial activity were declined.The anti-bacterial activities for S. aureus increased with the increases of lipophilicity and concentrations of HOU-C₈C_n.The results showed that the anti-bacterial activities of the compound with fork chains (HOU-C₈C₂ and HOU-C₈C₄) for S. aureus were weaker than the compounds with linear chains (HOU-C₁₀ and HOU-C₁₂).The anti-bacterial activity of HOU-C₈ and three HOU-C₈C_n for Gram-positive bacteria and Gram-negative bacteria were tested by Broth microdilution method. The target bacteria involved in this experiment were B. subtillis, E.coli, D. bacillus, T. bacillus, P. aeruginosa, Salmonella.The results indicated that the anti-bacterial activities of HOU-C₈C_n for Gram-positive bacteria were strong. The anti-bacterial activities of HOU-C₈C_n for B. subtillis were stronger than and those for. S. aureus.Whenα-H of octanoyl acetal was substituted by alkyl, the anti-bacterial activities of their products for B. subtillis were declined. MIC of HOU-C₈,HOU-C₈C₁,HOU-C₈C₂ and HOU-C₈C₄ were 62.5μg/ml,250μg/ml,125μg/ml and 32μg/ml, respectively.The anti-bacterial activities of HOU-C₈C_n for Gram-negative bacteria, such as D. bacillus and T. bacillus were weak and for E.coli, P.aeraginosa and Salmonella, the anti-bacterial activities of them were unobvious. Although not all the MIC of HOU-C₈C_n had not been tested, the absorbency indicated the same tendency that whenα-H of octanoyl acetal was substituted by alkyl, the anti-bacterial activities of their products for D. bacillus and T. bacillus were declined. The anti-bacterial activities increased with the increases of lipophilicity of HOU-C₈C_n. Anti-bacterial activities of HOU-C₈ for D. bacillus and T. bacillus were stronger than the anti-bacterial activities of HOU-C₈C_n MIC of HOU-C₈ and HOU-C₈C₄ for D. bacillus were both 250μg/ml, but HOU-C₈C₁ and HOU-C₈C₂ had not been tested. MIC of HOU-C₈,HOU-C₈C₁,HOU-C₈C₂ and HOU-C₈C₄ for T. bacillu were all 250μg/ml.The experiments in vitro suggested that whenα-H of octanoyl acetal was substituted by alkyl, the anti-bacterial activities of their products were declined, which maybe due to the charge density onα-C.The anti-bacterial activities increased with the increases of lipophilicity of HOU-C₈C_n.The lipophilicity on cell hemolysis, membrane fluidity and the structure of cell membrane would be the important factor for HOU-C₈C_n exerting the ant-bacteria function.The result that between two isomerides, the anti-bacterial activities of the compound with fork chains were weaker than the compounds with linear chains may be caused by two factors. One was the charge density onα-C and the other one was the influence of lipophilicity on cell hemolysis, membrane fluidity and the struoture of cell membrane.The anti-bacterial activities of HOU-C₈C_n for Gram-positive bacteria were stronger than for Gram-negative bacteria. It would be related with the quantity of peptidoglycan on cell wall of bacteria.