Antimicrobial activity of stereoisomers of cholanic acids’ derivatives compared to cholic acid.

Анотація

A series of membrane-active cationic derivatives of cholic acid with antimicrobial activity may have common aspects of the action mechanism with previously found cationicpeptide antibiotics. Bactericidal action of some substances was found for a wide range of gram-negative and grampositive microorganisms, other derivatives cholic acid were weakly active against gram-negative microorganisms, but effectively penetrated through the outer membrane and increased the sensitivity of bacteria to hydrophobic antibiotics.The negative feature of membrane-active antimicrobial agents is a frequent expressionof hemolytic
properties that may be an obstacle to their regular use. Level haemolyticity of bile acids derivatives ranged from very weakly hemolytic to high hemolytic. The aim of this work was to explore new stereomeric compounds: derivatives of bile acids with weak hemolytic activity and potentially high antimicrobial effect. According to previously conducted research on optical structure and pharmacological action of stereoisomers stereoisomers α / β-amino, it was found that bile acids change their pharmacological properties depending on the stereoconfiguration therefore to continue the analysis of bile acid derivatives it were taken already studied stereoisomers amino functionalized cholic acid.In 3D-models of 3β- amino-7α, 12α-dihydroxy-5β-cholanic acid has a more unfavorable position of the amino group at the 3rd carbon atoms and requires a large amount of activation energy and reaction conditions are more stringent than 3α-isomer need, so therefore bacterial metabolism blocking is possible through this mechanism. Thus reactions involving 3β-  amino group are complicated because of its shielding by  voluminous substituent at 10th position steranic fragment(CH3 group) in contrast to 3α-amino which is directed in the opposite direction. Materials and methods. The antimibicrobial activity was meseared by the method of serial dilutions in a solid  nutrient medium. To compare the effects of spatial configuration on the antimicrobial activity of substances we used 8 compounds (4 α-stereoisomers and 4 β- stereoisomers) with the same substituents, which were obtained by synthesis of corresponding α/β-amino cholanic
acid with acylchloride. Result and discussions. The results of antimicrobial
activity show that all studied drugs can be characterized by a wide spectrum of antibacterial properties against strains of aerobic bacteria and fungi and they have higher rate of growth delay compared to their 3α/β predecessors. αCyclBut showed a greater influence on growth delay of Candida albicans, Escherichia coli and Pseudomonas aeroginosa. Almost all of α isomers showed weaker antimicrobial activity against Proteus vulgaris, Bacillus subtilis, Staphylococcus aureus compared with their β analogues and in absolute values. Conclutions. All compounds have showed a wide range of antimicrobial activity and might be used as potential antibiotics. αCyclBut, βCyclBut, β3Me-Ph caused the greatest growth delay of microorganisms.