Design,Synthesis And Antibacterial Activity Of A Series Of Novel Indole Alkaloid Derivatives

In recent years,the lack of new antifungal drugs and severe resistance have led to high morbidity and associated mortality of fungal infections.However,the development of new drugs has been slow due to the limited availability of antifungal therapies,so finding alternative drugs with low resistance rates and few side effects remains a major challenge.Natural products have great potential in the research and development of new drugs,among which alkaloids,mainly as a class of nitrogenous organic compounds,are widely present in plants and Marine plants,and they show good biological activities against a variety of fungi and bacteria.This study to natural products evodia rutaecarpa alkali,hydrogen camel structure alkali,fascaplysin as the guide,designed and synthesized a series of antimicrobial activity of indole alkaloid derivatives,and evaluate its biological activity in vivo and in vitro and the mechanism of action,in order to get safe,effective mechanism and a clear resistance to fungal infection of lead compounds.The main contents include the following three parts:The first part: 31 evodiamine derivatives were designed and synthesized,and their antifungal activities against Trichophyton rubrum,Trichophyton mentagrophytes and Candida albicans were determined by in vitro antibacterial experiments.Both showed strong antifungal activity,and the effect was stronger than ketoconazole.In order to further study the antifungal effect and mechanism of compound A7,we confirmed that compound A7 not only has good antifungal activity,but also has multiple targets by bactericidal curve,XTT experiment,electron microscope experiment,RT-PCR experiment and transcriptome analysis.point.In addition,compound A7 can also exert a good antifungal effect in vivo.Part Ⅱ: Design and synthesis of 16 dehydrocamelin derivatives.The in vitro antifungal experiments show that compounds 3c,4d and 5a have certain effects on Candida albicans,but the other two fungi have weaker effects.To broaden the range of applications,we investigated their performance on bacteria.In vitro antibacterial experiments showed that some derivatives had better activity against Staphylococcus aureus,Staphylococcus albicans and MRSA compared with dehydrocamelinapine,among which the most effective compounds were compounds 3c and 5a.For further study,we plotted their bactericidal curves and conducted in vivo antibacterial experiments on compound 3c in mice,which also proved that it also has good antibacterial activity in vivo,TNF-α in the lungs of mice treated with 3c,the secretion levels of IL-1β,MCP-1 and IL-6 were significantly lower than those in the untreated group,consistent with the weakened inflammatory response after treatment.The third part: 20 fascaplysin derivatives were designed and synthesized,and the in vitro antifungal experiments were carried out on the fascaplysin derivatives.The results showed that compounds 6e,6f and 7e had a certain antibacterial effect on Candida albicans,but the effect was relatively weak.Therefore,we measured the antibacterial activity of the target compound against 5 kinds of bacteria by MIC(minimum inhibitory concentration test),and the experimental results showed that some derivatives had better antibacterial activity against Staphylococcus aureus,Staphylococcus albicans and MRSA compared with fascaplysin.Antibacterial activity,especially compounds 6e and 7e,so we further plotted the in vitro sterilization time curve,and compared with fascaplysin at the same concentration,compounds 6e and 7e can kill Staphylococcus aureus in a shorter time.To sum up,we synthesized a series of derivatives of evodiamine,dehydrocamelin and fascaplysin,and further evaluated their antibacterial activities.Finally,we found that compounds A7,3c,6e and 7e have good antibacterial activities,and also have good antibacterial activities.It provides a research basis for further modification and transformation of such compounds in the future.