Synthesis And Antibacterial Evaluation Of 2,2-disubstituted Indolin-3-ones

Indole is an aromatic heterocyclic organic compound.Indole derivatives are a very important type of heterocyclic compounds.2,2-disubstituted indolin-3-ones are core scaffolds of a wide range of bioactive molecules,and have also been widely used as key intermediates in the total synthesis of a variety of natural products.Therefore,great efforts have been devoted to the construction of these structures.Current syntheses are mainly based on four strategies,i.e.,the oxidative rearrangement of 2,3-disubstituted indoles,cyclization reactions from acyclic starting materials,direct transformation from corresponding 3H-indol-3-ones or indolin-3-ones,and oxidative dearomatization of indoles.At present,the research and development of antibacterial drugs is at a relatively low level,and few antibacterial drugs have been marketed in recent years.Even with new drugs on the market,drug-resistant strains will soon appear due to drug abuse.Therefore,there is an urgent need to continuously develop new antibiotics.In this paper,2,2-disubstituted indole-3-one indole derivatives were mainly synthesized with indole as substrate and their antibacterial activity was studied.In the second chapter,an oxidative cross-dehydrogenative coupling of indoles with 1,3-dicarbonyl compounds and indoles has been developed.The reaction proceeds smoothly under mild conditions and features a broad substrate scope with excellent functional group tolerance,affording structurally diverse 2,2-disubstituted indolin-3-ones in high yields.Oxidative dimerization or trimerization of indoles was achieved under the same conditions.Moreover,a variety of C-H nucleophiles such as pyrrole,thiophene,acetaldehyde,and acetone were also suitable substrates and all the 2,2-disubstituted indolin-3-ones were obtained as racemic molecules.In the third chapter,a series of 2,2-disubstituted indole-3-one bisindole derivatives were prepared on the basis of a hit compound(1)which was identified from a regular antimicrobial screening of an in-house small compound library,and then investigated for antibacterial activity.The results showed that most of them showed moderate to good antibacterial activity against two Gram-positive strains Staphylococcus aureus and Bacillus subtilis.In addition,all these compounds with a chiral center were obtained as racemates,in order to clarify whether the molecules show any biological differences at the enantiomeric level,we separated them via a chiral column and finally tested their antibacterial effects against Staphylococcus aureus and Bacillus subtilis.Finally,in the antibacterial activity test of the drug-resistant strain MRSA,the dihalogenated analogues(19x–z)displayed moderate grow inhibitory effect toward a drug-resistant strain MRSA without showing obvious cytotoxicity at the effective concentration.In conclusion,this paper has developed an effective method for the synthesis of 2,2-disubstituted indole-3-one indole derivatives.This method is simple,efficient,and highly practical.In addition,this paper has identified a new class of selective antibacterial drugs that can be used as lead compounds for the further development of new non-cytotoxic antibiotics in the future.