- Synthesis method of chloroindole hydrazide
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The invention relates to a synthesis method of chloroindole hydrazide, and belongs to the technical field of pesticides. The specific preparation method comprises the following steps: (1) uniformly mixing a compound shown as a formula (I), a solvent I, acetonitrile and a catalyst I, and then adding a hydrogen source for reaction; after the reaction is finished, treating to obtain a compound shown as a formula (II); (2) mixing the compound shown in the formula (II), (4-chlorphenyl) methylene hydrazine, a solvent II and a catalyst II for reaction, and after the reaction is completed, performing post-treatment to obtain chloroindole hydrazide; a novel synthetic route is provided, catalytic hydrogenation cyclization is performed on tryptophan or ester thereof and acetonitrile, and then reacts with (4-chlorphenyl) methylene hydrazine to obtain the chloroindole hydrazide through two steps. Compared with the prior art, the preparation method has the advantages of short synthesis steps, high reaction yield, no use of high-toxicity, strong-corrosivity and strong-irritation reagents, and convenience in realization of industrial production.
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Paragraph 0065-0068
(2022/03/18)
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- Discovery of pyridoindole derivatives as potential inhibitors for phosphodiesterase 5A: in silico and in?vivo studies
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The aim of this work was to synthesise derivatives from identified plant based pyridoindole lead scaffold, and to assess phosphodiesterase 5A inhibitory potential by in silico and in?vivo. Pyridoindole derivatives were synthesised by using six-stage reactor. In silico screening was carried out by grip-based docking methodology. In step-I, tryptophan as a starting material was reacted with different aldehydes and ketones to obtain 11 molecules. In step-II, obtained molecules were reacted with ethanol and benzyl alcohols to obtain D1 to D22 derivatives. In silico investigation resulted in best three molecules D12, D4 and D8 with promising BE score. Oral acute toxicity study of selected molecules resulted in LD50 value 500 mg/kg in rats. The result of in?vivo antihypertensive study shown that molecule D12 was found to be the best antihypertensive lead molecule. This study could be a best platform to tailor novel biomolecules for inhibiting phosphodiesterase 5A enzyme in hypertension management.
- Mali, Dipak P.,Gaikwad, Dinanath T.,Bhatia, Manish S.,Bhatia, Neela M.
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- Novel β-carboline-based indole-4,7-quinone derivatives as NAD(P)H: Quinone-oxidoreductase-1 inhibitor with potent antitumor activities by inducing reactive oxygen species, apoptosis, and DNA damage
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Eighteen new β-carboline-based indole-4,7-quinone derivatives (12a–i and 13a–i) were designed and synthesized, and their in vitro and in vivo antiproliferative activities were studied. Most of target compounds showed strong inhibition on three human tumor cells' proliferation. In particular, the most active compound 13g not only displayed more prominent antiproliferative activities than β-lapachone, a clinical antitumor candidate, but also exerted significant NAD(P)H: quinone-oxidoreductase-1 (NQO1) inhibitory activity and NQO1-dependent cytotoxicity in HT29 cells. Furthermore, 13g dose-dependently induced high ROS levels in HT29 cells, and selectively inhibited cancer cell but not non-tumor colon cell proliferation in vitro. Importantly, 13g promoted HT29 cell apoptosis and DNA damage by regulating relative apoptotic proteins and H2AX expression. Finally, 13g displayed significant growth inhibition of HT29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.
- Guo, Yibing,Xu, Liancheng,Ling, Changchun,Yang, Tao,Zheng, Wenjie,Lv, Jin,Guo, Qingsong,Chen, Bohua
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p. 1433 - 1446
(2020/07/13)
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- β-Carboline and N-hydroxycinnamamide hybrids as anticancer agents for drug-resistant hepatocellular carcinoma
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In an effort to develop anticancer agents that may overcome drug resistance, the number one reason in caner death, we have developed a series of novel hybrids of β-carboline and N-hydroxycinnamamide as histone deacetylase (HDAC) inhibitors. Most of the hybrids 13a-p showed strong antiproliferative effects with low-micromolar IC50 values against four human cancer cells. The most potent compound of series 13p exhibited high HDAC1/6 inhibitory effects, and also increased the acetylation levels of histone H3, H4 and α-tubulin. Importantly, 13p demonstrated high anticancer potency against drug-sensitive HepG2 and Bel7402 cells and drug-resistant Bel7402/5FU cells. Hybrid 13p triggered significant apoptosis by regulating apoptotic relative proteins expression in these Bel7402/5FU cells. Finally, 13p induced a substantial amount of autophagic flux activity by the accretion of the expression of LC3-II and the degeneration of expression of p62 and LC3-I in Bel7402/5FU cells. Overall, 13p is a novel β-carboline/N-hydroxycinnamamide hybrid with significant anticancer potency that warrants further evaluation for the treatment of drug-resistant hepatocellular carcinoma.
- Ling, Yong,Gao, Wei-Jie,Ling, Changchun,Liu, Ji,Meng, Chi,Qian, Jianqiang,Liu, Siqun,Gan, Huiling,Wu, Hongmei,Tao, Jinhua,Dai, Hong,Zhang, Yanan
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p. 515 - 526
(2019/03/08)
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- Synthesis and biological evaluation of novel N9-heterobivalent β-carbolines as angiogenesis inhibitors
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A series of novel N9-heterobivalent β-carbolines has been synthesized. All the novel compounds were tested for their anticancer activity against six tumour cell lines in vitro. Among these molecules, compounds 5b, and 5w exhibited strong cytotoxic activities with IC50 value of lower than 20 μM. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 5b and 5w exhibited that tumour inhibition rate of over 40% in the Sarcoma 180 and Lewis lung cancer animal models. Preliminary structure–activity relationships (SARs) analysis indicated that: (1) C1-methylation and C7-methoxylation were favorable for increased activities; (2) 3-Pyridyl or 2-thienyl group substituent into position-1 of the β-carboline core, and the aryl substituent into another β-carboline ring might be detrimental to cytotoxic effects of this class compounds. Investigation of the preliminary mechanism of action demonstrated that compound 5b had obvious angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay.
- Guo, Liang,Ma, Qin,Chen, Wei,Fan, Wenxi,Zhang, Jie,Dai, Bin
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p. 375 - 387
(2019/01/10)
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- Synthesis and structure-activity relationships of asymmetric dimeric β-carboline derivatives as potential antitumor agents
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A series of newly asymmetric dimeric β-carbolines with a spacer of 4–6 methylene units between the indole nitrogen and the harmine oxygen were synthesized. Structures of all the novel synthesized compounds were confirmed by their spectral and analytical studies. All of the synthesized compounds were screened for their in vitro cytotoxic activity against nine cancer cell lines. The results revealed that compounds 7c, 7o and 7s exhibited the highest cytotoxic activities with IC50 values of less than 20 μM against the tumor cell lines tested. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, and compound 7o exhibited potent antitumor activities with the tumor inhibition rate of over 40%. The wound healing assay displayed a specific impairment in the motility of the HT-29 cells, which suggested the anti-metastatic potential of compound 7o. Moreover, compound 7o had obvious angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay. Preliminary structure-activity relationship (SAR) analysis indicated that: (1) 3-phenylpropyl substituent at the N9-position of the indole ring was the most suitable group giving rise to potent cytotoxic agents; (2) the spacer length affected the antitumor potencies, and four methylene units were more favorable.
- Guo, Liang,Chen, Wei,Cao, Rihui,Fan, Wenxi,Ma, Qin,Zhang, Jie,Dai, Bin
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p. 253 - 265
(2018/02/15)
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- Design, synthesis, and antifungal activity of novel aryl-1,2,3-triazole-β-carboline hybrids
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The copper catalytic azide and terminal alkyne cycloaddition reaction, namely “click chemistry”, gives a new and convenient way to create l,4-disubstitutd-l,2,3-triazoles. In this work, 2-pyrrolecarbaldiminato–Cu(II) complexes were established as efficient catalysts for the three-component 1,3-dipolar cycloaddition reaction of arylboronic acid and sodium azide (NaN3) with terminal alkynes in ethanol at room temperature to 50 ?C, 1,4-disubstituted 1,2,3-triazoles were synthesized. Following the optimized protocol, two series of new aryl-1,2,3-triazole-β-carboline hybrids have been designed and synthesized, and the chemical structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). All of the target compounds were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Fusarium oxysporum, Botrytis cinerea Pers., sunflower sclerotinia rot, and rape sclerotinia rot by mycelia growth inhibition assay at 50 μg/mL. The antifungal evaluation of the novel hybrids showed that, among the tested compounds, 5a, 5b, 5c, and 9b showed good antifungal activity against sunflower sclerotinia rot. Specifically, compound 9b also exhibited high broad-spectrum fungicidal against all the tested fungi with inhibition rates of 58.3%, 18.52%, 63.07%, 84.47%, and 81.23%. However, for F. oxysporum, all the target compounds showed no in vitro antifungal activities with an inhibition rate lower than 20%. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents.
- Huo, Xin-Yu,Guo, Liang,Chen, Xiao-Fei,Zhou, Yue-Ting,Zhang, Jie,Han, Xiao-Qiang,Dai, Bin
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- A seed of common peganum alkali nenzoyl urea compound, and its preparation method and application
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The invention discloses banisterine benzoyl urea compounds and a preparation method and application thereof. The banisterine benzoyl urea compounds have a structural formula I shown in the specification; in the formula I, R1 can be methyl, phenyl, 3,4,5- triethoxy phenyl, p-methoxyphenyl or p-chlorphenyl, R2 can be H or Br, and X can be O or S. The banisterine benzoyl urea compounds have an outstanding insecticidal activity for Culex fatigans, prodenia litura and Chilo suppressalis; a part of the compounds are identical to a control insecticide Dibenzoyl-1-tert-butylhydrazine in term of activity; the banisterine benzoyl urea compounds have good inhibitory activity for rice sheath blight disease, alternaria solani, Collectotrichum musae, grey mould fruit rot of strawberry and sour rot pathogenic bacteria of citrus; a part of the compounds have better inhibitory activity for the above five phytopathogens than validamycin. The banisterine derivatives are simple in structure and easy to synthesize; the synthesis process is simple, the product purity is high; the banisterine benzoyl urea compounds and the preparation method thereof are suitable for large-scale industrial popularization and application.
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Paragraph 0050; 0051
(2016/10/09)
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- Synthesis and preliminary evaluation of novel alkyl diamine linked bivalent β-carbolines as angiogenesis inhibitors
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A series of novel bivalent β-carbolines linked with an alkyl diamine spacer at the C-3 position were synthesized and evaluated as potent angiogenesis inhibitors. The results demonstrated that most bivalent β-carbolines displayed significant anti-proliferative effects against EA.HY926 human umbilical vein cell lines. Compound 8z was found to be the most potent anti-proliferative agent with an IC50 value of 1.10 μM against EA.HY926 cell lines. Preliminary investigations on the mechanisms of action revealed that compound 8z could dramatically inhibit EA.HY926 cell migration and tube formation in a dose-dependent manner. Moreover, compound 8z exhibited significant angiogenesis inhibitory effects in CAM assay, and the anti-angiogenic potency was comparable with that of the reference drug Endostar. These molecules might serve as candidates for further development into vascular-targeting antitumor drugs.
- Guo, Liang,Chen, Wei,Fan, Wenxi,Ma, Qin,Sun, Rongqin,Shao, Guang,Cao, Rihui
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supporting information
p. 2177 - 2183
(2016/11/18)
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- Synthesis and biological evaluation of piperazine group-linked bivalent β-carbolines as potential antitumor agents
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A series of novel bivalent β-carbolines with a piperazine group spacer between 3-methylene units were synthesized and evaluated as antitumor agents. The results demonstrated that compounds 7e and 7g exhibited the most potent cytotoxic activities against ten tumor cell lines. Structure-activity relationships analysis indicated that (1) the substituents in positions 1 and 9 of the β-carboline ring played a significant role in modulating the antitumor activity; (2) the introduction of alkyl groups into position-9 of the β-carboline nucleus enhanced their cytotoxic potencies and the butyl substituent was the optimal group. Investigation of the preliminary mechanism of action demonstrated that compound 7g showed obvious anti-angiogenic activity in the in vivo CAM assay, and the potency was similar to that of CA4P (200 μM).
- Sun, Rongqin,Liu, Rui,Zhou, Chi,Ren, Zhenghua,Guo, Liang,Ma, Qin,Fan, Wenxi,Qiu, Liqin,Yu, Huijuan,Shao, Guang,Cao, Rihui
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supporting information
p. 2170 - 2174
(2015/12/11)
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- Synthesis and herbicidal activity evaluation of novel β-carboline derivatives
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Based on the original structure of harmine, several novel 1,2,3,4-tetrahydro-β- carboline, β-carboline and 1-substituted-β- carboline derivatives bearing a substituted carbohydrazide group at C-3 were designed and synthesized to investigate the structureactivity relationship of their analogues. All of the compounds were characterized by infrared (IR), proton and carbon nuclear magnetic resonance (1H-NMR, 13C-NMR), and mass spectroscopy (MS). The bioassay tests showed that N'-benzylidene-1-phenyl-β- carboline-3-carbohydrazide (C25H 18N4O, m.w. 390.4) (c2) and N'-(4- trifluoromethylbenzylidene)- 1-phenyl-β-carboline-3-carbohydrazide (C26H17N4OF3, m.w. 458) (d2) exhibited good inhibitory activity against dicotyledonous and monocotyledonous weeds, with EC50 values of 4.83 μM and 14.25 μM, respectively.
- Weng, Qunfang,Huang, Jingfei,Zeng, Yong,Deng, Yueye,Hu, Meiying
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experimental part
p. 3969 - 3980
(2012/09/10)
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- Cytotoxic and insecticidal activities of derivatives of harmine, a natural insecticidal component isolated from peganum harmala
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In a continuing effort to develop novel β-carbolines endowed with better insecticidal activity, a simple high-yielding method for the synthesis of harmine compounds starting from L-tryptophan has been developed and a series of 1,3-substituted β-carboline derivatives have been synthesized and evaluated for their cytotoxicity against insect cultured Sf9 cell line in vitro and insecticidal activities against 4th instar larvae of mosquitos, Culex pipiens quinquefasciatus and mustard aphid, Lipaphis erysimi. The results demonstrated that 1-phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (compound 2) and methyl 1-phenyl-β-carboline-3-carboxylate (compound 13) represented the best potential compounds, with Sf9 cells inhibition rates of 71.55% and 60.21% after 24 h treatment at concentrations of 50-200 mg/L, respectively. Both compounds 2 and 13 also showed strong insecticidal activity towards 4th instar larvae of mosquitos with LC50 values of 20.82 mg/L and 23.98 mg/L, and their LC90 values were 88.29 mg/L and 295.13 mg/L, respectively. Furthermore, the LC50 values of compounds 2 and 13 against mustard aphids were 53.16 mg/L and 68.05 mg/L, and their LC 90 values were 240.10 mg/L and 418.63 mg/L after 48 h treatment. The in vitro cytotoxicity of these compounds was consistent with the insecticidal activity in vivo. The results indicated that the 1- and 3-positions of the β-carboline ring deserve further investigation to develop biorational insecticides based on the natural compound harmine as a lead compound.
- Zeng, Yong,Zhang, Yaomou,Weng, Qunfang,Hu, Meiying,Zhong, Guohua
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experimental part
p. 7775 - 7791
(2011/03/19)
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- HARMINE DERIVATIVES, INTERMEDIATES USED IN THEIR PREPARATION, PREPARATION PROCESSES AND USE THEREOF
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This invention relates to compounds of general formula (I), wherein R1, R2, R3, R4 and R5 are as defined specification; intermediates used in their preparation, preparation processes and use thereof. The present invention produce harmine derivatives with enhanced antihumour activity and lower nervous system toxicity by structurally modification parent structure of β-carboline of harmines at position 1, 2, 3, 7 and 9, The compounds of the present invention can be pre easily with high yield. They can be used in manufacture of a variety of antitumour medicines and medicines used in treatm tumour diseases in combination of light or radiation therapy.
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Page/Page column 14; 15; 95
(2008/06/13)
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- Isolation of mutagenic β-carboline derivatives after nitrite treatment of maillard reaction mixtures and analysis of these compounds from foodstuffs and human urine
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Mixtures of carbohydrate decomposition products and L-tryptophan were incubated at pH 7.0 and 37°C for 4 weeks. These mixtures exhibited mutagenic activity toward S. typhimurium TA 100 without metabolic activation after a nitrite treatment at pH 4.0. Four β-carboline derivatives were isolated as premutagens from mixtures of methylglyoxal and furfural. These premutagens were also found to be contained in daily foodstuffs and human urine samples.
- Masuda, Shuichi,Kanamori, Hisayuki,Kinae, Naohide
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p. 2232 - 2235
(2008/02/03)
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- Synthesis and biological evaluation of novel β-carboline derivatives as Tat-TAR interaction inhibitors
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Four new β-carboline derivatives were synthesized bearing guanidinium group or amino group-terminated side chain targeting the TAR element. Compounds 5 and 6 with terminal guanidinium group showed inhibitory activities on Tat-TAR interaction as well as to HIV-1 in MT4 cells. Furthermore, capillary electrophoresis assay implied that compound 6 could not only bind to TAR but also hinder the Tat-TAR interaction.
- Yu, Xiaolin,Lin, Wei,Li, Jingyun,Yang, Ming
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p. 3127 - 3130
(2007/10/03)
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