Design,Synthesis And Bioactivity Of Novel Diketopiperazines Based On Brevianamide F

Indole diketopiperazines have a wide range of biological activities,including anticancer activity,immunomodulatory activity,antifungal activity and insecticidal activity.They can also act as plant growth regulators.Brevianamide F was reported as a new natural plant growth inhibitor and could serve as scaffold for many complex indole diketopiperazines.Variation of the amino acid precursors will lead to many diketopiperazines exhibiting various biological activities.Herein,four stereoisomers of the natural product(indole-N-isoprenyl)tryptophan-valine diketopiperazine were accomplished.Based on the these natural products and Brevianamide F,design and synthesis of novel indole diketopiperazines alkaloids and analogues were carried out.Biological exploration and SAR were also conducted,and the results obtained are as follows:(1)Synthesis of the four stereoisomers of natural product(indole-N-isoprenyl)tryptophan-valine diketopiperazine was achieved from cheap and easily available tryptophan and valine in 5 steps.The key steps consisted of protection and condensation of different amino acids,followed by deprotection and cyclization.The structures were identified by electrospray ionization mass spectrometry(ESI-MS),1H-Nuclear Magnetic Resonance(1H-NMR)Spectroscopy,13C-Nuclear Magnetic Resonance(13C-NMR)Spectroscopy.The in vitro antifungal bioactivity of these compounds were tested against 7 important plant pathogens including Fusarium graminearum.Gaeumannomyces gramini,Botrytis cinerea,Phytophythora capsici,Rhizoctonia solani,Sclerotinia sclerotiorum,Pyricularia oryzae.The antifungal activity of the stereoisomer from the amino acids is superior to the enantiomer and diastereoisomers.The results from spore germination against Pyricularia oryzae was consistent with that of mycelium growth rate method.The(9R,12S)-stereoisomer(1a),(9R,12R)-stereoisomer(1b),(95,12R)-stereoisomer(1c)and(9S,12S)-stereoisomers(1d)were obtained and tested against Pyricularia oryzae with the inhibitory rates of 68.84%,78.45%,63.54%and 59.54%,respectively.(2)with the(9R,127R)-stereoisomer(1b)as a lead,Structure optimization was carried out and investigated considering the effects of the open-loop and closed-loop structures on the activity.25 novel indole diketopiperazines were synthesized and characterized by electrospray ionization mass spectrometry(ESI-MS),1H-NMR and 13C-NMR.The antifungal activity was conducted against 7 important plant pathogens,including Fusarium graminearum.Gaeumannomyces gramini,Botrytis cinerea,Phytophythora capsici,Rhizoctonia solani,Sclerotinia sclerotiorum,Pyricularia oryzae.obvious effect of substituents and chirality on bioactivity were detected.Compound 2g was selected as an antifungal lead against Sclerotinia sclerotiorum,the in vivo biotest also showed that compound 2g possessed good preventative efficacy at 100 mg/L against Sclerotinia sclerotiorum with the inhibitory rate of 41.9%.(3)Regulatory bioactivities of compounds 1b,2g,and 2j were measured on the roots and shoots of Echinochloa crus-galli and Eclipta prostrata.The results showed that compound 2g can inhibit the growth of roots of Eclipta prostrata significantly at the concentration of 100 mg/L,with the inhibitory rate of 46.4%.Compound 2j had a promoting effect on the growth of roots of Eclipta prostrata,with the concentration ranging from 200 mg/L to 0.125 mg/L,which was different from that of the positive control indole acetic acid,changing the effect from inhibition to promotion with the reduction of concentration.In summary,synthesis of the four stereoisomers of the natural product(indole-N-isoprenyl)tryptophan-valine diketopiperazine was completed 30 indole diketopiperazines were synthesized based on Brevianamide F and(indole-N-isoprenyl)tryptophan-valine diketopiperazine including 27 new compounds.antifungal activities,structure-activity relationship and plant growth regulatory activities were also explored.This work laid a good foundation for the discovery of new chiral diketopiperazines as potential agrochemicals.