Design, Synthesis And Antibacterial Activity Of Novel Andrographolide Derivatives

ObjectivesDesign and synthesis of new andrographolide derivatives. SAR investigation of andrographolide class of compounds.Methods1. Chemical synthesis of new andrographolide derivatives.2. Characterize structures by1H-NMR, ESI-MS and elemental analysis.3. MIC determination by disc method. Experiments were performed to investigate inhibition of bacteria quorum sensing.Results1. A series of andrographolide derivatives were synthesized through a facile condensation reaction with different carboxylic acids.2. To find if the new compounds directly inhibit bacterial growth, we used the zone of inhibition method to measure the inhibition of P. aeruginosa growth. Andro, AL-1 and the new compounds were not active against P. aeruginosa growth at a concentration of 1 mM. AL-1 and 11b inhibited PA growth at 2 mM, and andro showed inhibition at 4 mM.3. All compounds tested inhibited production of pyocanin and exoproteinases. For inhibition of pyocanin production, compound 11b and AL-1 were the most potent. Compounds 3b-10b significantly inhibited pyocyanin production, and all were more potent than the natural Andro. In the inhibition of proteinases assay, compounds AL-1,5b,8b and 11b almost completely suppressed protease production, Compounds 7b,9b,10b and Andro had similar activity.4. The relationship of new structure and antibacterial activity was summarized. ConclusionAll the new compounds inhibit the virulence factor release by suppressing the QS system of gram-negative bacterial Pseudomanas aeruginosa. The fact that AL-1, with a disulfide bond, and compound 11b, without a disulfide bond, are equally effective inhibiting the productions of pyocyanin and protease suggests that the disulfide bond plays insignificant role for antibacterial activity.