Synthesis And Bioactivity Study And SAR Of Natural Product Harmaline And Harmine And Their Derivatives

Natural products especially plant derived natural products have the following advantages:novel and diverse structures, and difficulty to produce resistance due to the unique mode of action; possibility to find new targets; easily absorbed by plants and degradable in the environment, so good environmental compatibility. Hence, pesticide discovery based on natural products has been the most important approach.Carboline alkaloids are a large source of natural alkaloids, which can be divided into α, β,γ,δ-carbolines according to the different positions of the nitrogen atom of the pyridine ring. Wherein β-carboline alkaloids are the most widely distributed in nature, the largest number, and the most in-depth study. In this paper, harmaline and harmine are chosed as our object of study, our works focus on the synthetic methodology, structural diversity, biological activity and structure-activity relationship.In the synthesis methodology, two methods were developed respectively for the synthesis of tetrahydro-β-carboline and spiro [indoline-3,3’-quinoline] skeleton:An efficient method, based on an unexpected discovery, for the construction of tetrahydro-β-carboline skeleton was developed via I2-promoted cascade electrophilic cyclization. The reaction mechanism of this reaction was studied, and this method was used in the synthesis of/β-carboline alkaloid Oxopropaline G sucessfully.An efficient method to prepare1’H-spiro[indoline-3,3’-quinoline] and their trifluoromethylated products was developed via a palladium-catalyzed cascade reaction. The amount of water in the reaction system played an important role in the in situ trifluoromethylation reaction. The in situ trifluoromethylation exhibited excellent stereoselectivity via molecular self-induced. The reaction mechanism of this reaction was also studied.In terms of biological activity, five categories of β-carboline derivatives were designed and synthesized, the biological activities of these compounds were studied systematically, and QSAR was summarized. A group of compounds exhibited high anti-TMV activity was developed, and these compounds have good prospect for further development:Firstly, six known β-carboline, dihydro-β-carboline, and tetrahydro-β-carboline alkaloids, and a series of derivatives of β-carboline-3-carboxylic acid and Harmol were designed, synthesized, and first evaluated for their anti-TMV activities both in vitro and in vivo, fungicidal and insecticidal activities. These natural products Harmane, Harmalan, Tetrahydroharmane, Terahydroharmine, and (1S,3S)-ethyl1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-&]indole-3-carboxylate (5-7)(46.5,50.4,43.9, and47.9%,500μg/mL) exhibited higher antiviral activities than Ribavirin (40.0,37.4,36.2, and38.5%,500μg/mL). In terms of fungicidal activity,6-brominated Harmane (Ⅴ-1),8-nitro Harmane (Ⅴ-4) and Hannane containing pivaloyloxy at7-position (Ⅴ-9) exhibited more than70%inhibition rate against Cercospora arachidicola Hori, Physalospora piricola, Sclerotinia sclerotiorum, Bipolaris maydis, Watermelon-anthracnose, Phytophthora capsici, and Rhizoctonia solani at50mg/kg. In the insecticidal activity, the6-nitro Harmane (Ⅴ-3), Ⅴ-9, and1-methyl-N-(piperidin-1)-9H-pyrido [3,4-b] indole-3-carboxamide (Ⅴ-16) exhibited more than50%insecticidal activity against mosquito larvae at5mg/kg.By drawing the creation ideas of botanical pesticides, and using (1S,3S)-1-methyl-2,3,4,9-tetrahydro-β-carboline-3-carboxylate (5-7\Ⅵ-7), which have been found exhibited good anti-TMV activity by us, as a lead compound, a series of derivatives were designed and synthesized, and the anti-TMV, fungicidal and insecticidal activities of these compounds were tested. We found that the anti-TMV activities of compounds Ⅵ-7,(1S,3S)-butyl1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (VI-9),(S)-ethyl2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-3-carboxylate (Ⅵ-10),(1S,3S)-ethyl1-(pyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (VI-12),(S)-ethyl1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole-3-carboxylate (Ⅵ-14), and (1S,3S)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide (Ⅵ-15) were better than Ribavirin (40.0,37.4,36.2, and38.5%,500μg/mL), in particular the activities of (VI-9)(48.2%,51.3,42.2, and43.2%,500μg/mL) and (Ⅵ-15)(50.0,46.0,48.2, and49.6%,500μg/mL) were better than that of the lead compound VI-7(46.5,50.4,43.9, and47.9%,500μg/mL). We also found the fungicidal activities of compound VI-9 exhibited more than70%inhibition rate against Cercospora arachidicola Hori, Alternaria solani, Bipolar is maydis, and Rhizoctonia solani at50mg/kg, and compounds Ⅵ-7and Ⅵ-12exhibited more than60%insecticidal activity against mosquito larvae at5mg/kg.Using (1S,3S)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole-3-carbo-hydrazide (Ⅵ-15), which have been found exhibited good anti-TMV activity by us, as a lead compound, tetrahydro-β-carboline compounds containing hydrazone and bishydrazide structure were designed and synthesized through the introduction of active fragments. For compounds containing hydrazone structure, the anti-TMV activity of most of the compounds was better than that of the lead compounds VI-15(50.0,46.0,48.2, and49.6%,500μg/mL), and significantly better than that of Ribavirin. The activities of compounds Ⅶ-6, Ⅶ-9, Ⅶ-13, Ⅶ-25, Ⅶ-26, and Ⅶ-27were better than that of novel anti-plant viral agent NK-007(70.2,68.5,66.8, and67.9%,500μg/mL), which was created by our lab. For compounds containing bishydrazide structure, the activity of compound Ⅶ-33(52.1,44.1,54.5, and58.3%, at500μg/mL) was better than that of the lead compound Ⅵ-15, the other compounds exhibited an equivalent or reduced activities compared with the lead compound. In terms of fungicidal activity, these two kinds of compounds exhibited good fungicidal activities against14kinds of fungi, in particular the compound Ⅶ-3-Ⅶ-6, Ⅶ-8, and Ⅶ-15exhibited more than70%inhibition rate against Physalospora piricola, Sclerotinia sclerotiorum, Rhizoctonia cerealis, and Botrytis cinerea at50mg/kg, especially the compounds (3S,E)-N’-(4-tert-butylbenzylidene)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] ind ole-3-carbohydrazide (Ⅶ-3) and (3S,E)-N’-(3,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide (Ⅶ-8) exhibited more than70%inhibition rate against11kinds of fungi at50mg/kg. The compound containing the structure of bishydrazide (Ⅶ-33-Ⅶ-39) exhibited an equivalent anti-TMV activities to that of the lead compound (Ⅵ-15). The insecticidal activity of these compounds against helicoverpa armigera, mythimna separate, and ostrinia nubilalis were not high. However, some of the compounds containing hydrazone showed good activity against mosquito larvae, e.g. the compound Ⅶ-1and VII-20 exhibited more than80%insecticidal activity at5mg/kg.Finally, according to the latest research work on the biogenetic synthesis of β-carboline and using the reverse thinking strategies, tryptophan and its derivatives were synthesized, and the biological activities and structure-activity relationships were studied. The bioassay showed that these compounds exhibited good activities against tobacco mosaic virus, the activities of compounds Ⅷ-3, Ⅷ-7, Ⅷ-9, Ⅷ-16, Ⅷ-18, and Ⅷ22were significantly higher than that of Ribavirin, especially the activity of (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (Ⅷ-7)(63.3,67.1,68.7, and64.5%,500μg/mL) was equivalent to that of NK-007. We also tested fungicidal and insecticidal activity of these compounds, and found the fungicidal activities of (2S)-2-amino-3-(1//-indol-3-yl)-N-((tetrahydrofuran-2-yl)methyl)propanamide (Ⅷ-13) exhibited more than80%inhibition rate against Cercospora arachidicola Hori, Alternaria solani, Bipolar is maydis, Physalospora piricola, Sclerotinia sclerotiorum, and Rhizoctonia cerealis at50mg/kg, and L-Tryptophan, VI-7, and VI-12exhibited more than70%insecticidal activity against mosquito larvae at5mg/kg.