Synthesis and antibacterial activity of spiro[4H-pyran-3,3'-oxindoles] catalyzed by Tröger's base derivative.

objective 1. Two class of spiro[4H-pyran-3,3'-oxindole] derivatives were prepared via the one-pot reaction of chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins and malononitrile successfully and which effectively catalyzed by a Tröger's base derivative 1b (5,12-dimethyl-3,10-diphenyl-bis-1H-pyrazol[b,f][4,5]-1,5-diazadicyclo[3.3.1]-2,6-octadiene). 2. The anti-bacterial activity of products against three wild-type bacteria (B. subtilis, S. aureus and E. coli) and two resistant strain (Methicillin-resistant S. aureus (18H8) and E. coli carrying the BlaNDM-1 gene (18H5) was evaluated using the minimum inhibitory concentration (MIC) method. Methods 1. 1-Phenyl-1,3-butanedione 2 or dibenzoylmethane 2' (0.42 mmol), substituted isatin 3 (0.4 mmol), malononitrile 4 (0.8 mmol), Tröger's base derivative 1b (0.08 mmol) and 10 mL of acetonitrile were added to a 50 mL round bottom flask and refluxed. After the completion (TLC monitoring), poured water (10 mL) into the reaction mixture, adjusted the pH = 7 with saturated NaHCO3 (aq.), then extracted the mixture with CH2Cl2 (50 mL × 3). Combined and dried the organic layers with anhydrous Na2SO4, removed the solvent under vacuum, purified the residue by column chromatography (VDCM : V MeOH = 80 : 1) to give product 5. 2. The evaluation of anti-bacterial activity was carried out by MTT method. Result 1. Seventeen spiro[4H-pyran-3,3'-oxindole] derivatives were synthesized through the reaction of chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins and malononitrile in one-pot in medium to high yields. 2. Four compounds showed antibacterial activity, and two of them showed the same activity as the positive control Ceftazidime on S. aureus (MIC = 12.5 μg/mL). Conclusion Two class of spiro[4H-pyran-3,3'-oxindole] derivatives were prepared and their anti-bacterial activity was evaluated. Tröger's base derivative 1b (5,12-dimethyl-3,10-diphenyl-bis-1H-pyrazol[b,f][4,5]-1,5-diazadicyclo[3,3,1]-2,6-octadiene) was used as efficient organocatalyst for the reaction of low reactive chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins and malononitrile in one-pot successfully and effectively by providing multiple active sites and alkaline environment. By the theoretical calculation, we explained the possible reaction sequence and the possible reaction mechanism. Due to the superiority and high efficiency of the TB framework as organocatalyst, the reaction showed many advantages including mild reaction conditions, low catalyst loading and wide substrate range. It expanded the application of Tröger's base to the multicomponent reaction in organocatalysis. Some products were screened out due to their high anti-bacterial activity in vitro, which showed their potential in new anti-bacterial drug development.