Synthesis And Antimicrobial Activity Of Aromatic-Substituented Spiro-Indolyl Diketopiperazines

Aromatic-subspirotryprostatin spiro-indolyl diketopiperazine is a kind of important parts of spiro-indolyl diketopiperazine,and spirotryprostatin alkaloids are the representative of spiro-indolyl diketopiperazine.The study found that these compounds have significant physiological and pharmacological activities,especially the inhibitory activity to cell cycle.All of these suggest that spirotryprostatin alkaloids can be used as the precursor compounds for new drug screening.Therefore,the framework of spirotryprostatin alkaloids was modified in this paper,and a series of aromatic-subspirotryprostatin spiro-indolyl diketopiperazine compounds were synthesized and their antimicrobial activities were studied.Our synthesis commenced with the commercial glycine and isatin,twelve kinds of Schiff base as dipole and thirteen kinds of(E)-3-arylideneindolin-2-one compounds as dipolarophile were prepared in two steps,respectively.Then the 1,3-dipolar cyclcyoaddition of(E)-3-benzylideneindolin-2-one to Schiff bases were accured respectively when the chiral auxiliary(S)-TF-Bipham-Phos and AgOAc were used as catalyst,and twelve spirooxindole-pyrrolidines were obtained.With the key intermediates spirooxindole-pyrrolidines in hand,the synthesis of spirotryprostatin required coupling of the spirooxindole-pyrrolidines with proline,acylation of the hindered amine with Fmoc-L-Pro-Cl and deprotection of the Fmoc-group,which resulted immediately in triggering of therequisite dipeptide,in this way,the desired products 9a-9e were smoothly obtained,all of which were reported for the first time.All compounds were characterized by 1H-NMR,13C-NMR,infrared spectrum,elemental analysis and ESI-HRMS,and the stereochemistry configuration of intermediates and final products were analysized via 2D NMR and X-ray diffraction analysis.Four strains of bacteria(Gram-positive: Staphy lococcus aureus,Streptococcus lactis;Gram-negative: Escherichia coli,Pseudomonas aeruginosa)and ten strains of fungi(Fusarium graminearum,Botrytis cinerea,Valsa mali,Alternaria alternate,Alternaria brassicae,Setosphaeria turcica,Peony anthracnose,Sclerotinia sclerotiorum,Phytophthora capsici,Colletotrichum gloeosporioides)were selected.The bioassay results demonstrated that all intermediates and final products have the antimicrobial activities with different degrees.It was found that target products showed better activity when compared to corresponding intermediates,moreover,all compounds showed a better antibacterial activity than antifigual activity.Obviously,further studies are required for understanding the antibacterial mechanism.