- Synthesis and evaluation of aryl substituted propyl piperazines for potential atypical antipsychotic activity
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Background: Schizophrenia is a disorder with complex etiology with hyperdopaminer-gia as the leading underlying cause. Atypical antipsychotics are the agents which do not give rise to significant extrapyramidal side effects and are more effective against negative symptoms of schizophrenia. Introduction: A new series of chloro-substituted substituted aryloxypiperazine derivatives and their indole based derivatives was designed and evaluated for atypical antipsychotic activity based on established models for combined dopaminergic and serotonergic antagonism. Method: The present series of compounds were designed based on 3D similarity studies, synthesized and evaluated for atypical antipsychotic activity in animal models for combined dopaminer-gic and serotonergic antagonism. The blood-brain barrier penetration potential was assessed from theoretical log BB values computed through an online software program. Results: Theoretical ADME profiling of the designed compounds based on selected physicochem-ical parameters suggested excellent compliance with Lipinski’s rules. The log BB values obtained for the compounds suggested a good potential for brain permeation. Indole substitution contributed towards an improved efficacy over aryloxy analogs. Lead compounds showed a potential for combined dopaminergic and serotonergic antagonism. Conclusion: The 5-methoxy indole based compounds 16 and 17 were identified as the lead compounds displaying a potential atypical antipsychotic profile.
- Singh, Shalu,Bali, Alka,Peshin, Tania
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p. 429 - 441
(2021/03/26)
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- Design, Synthesis, and Antifungal Activity of 2,6-Dimethyl-4-aminopyrimidine Hydrazones as PDHc-E1 Inhibitors with a Novel Binding Mode
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A series of novel 2,6-dimethyl-4-aminopyrimidine hydrazones 5 were rationally designed and synthesized as pyruvate dehydrogenase complex E1 (PDHc-E1) inhibitors. Compounds 5 strongly inhibited Escherichia coli (E. coli) PDHc-E1 (IC50 values 0.94-15.80 μM). As revealed by molecular docking, site-directed mutagenesis, enzymatic, and inhibition kinetic analyses, compounds 5 competitively inhibited PDHc-E1 and bound in a "straight"pattern at the E. coli PDHc-E1 active site, which is a new binding mode. In in vitro antifungal assays, most compounds 5 at 50 μg/mL showed more than 80% inhibition against the mycelial growth of six tested phytopathogenic fungi, including Botrytis cinerea, Monilia fructigena, Colletotrichum gloeosporioides, andBotryosphaeria dothidea. Notably, 5f and 5i were 1.8-380 fold more potent against M. fructigena than the commercial fungicides captan and chlorothalonil. In vivo, 5f and 5i controlled the growth of M. fructigena comparably to the commercial fungicide tebuconazole. Thus, 5f and 5i have potential commercial value for the control of peach brown rot caused by M. fructigena.
- Zhou, Yuan,Zhang, Shasha,Cai, Meng,Wang, Kaixing,Feng, Jiangtao,Xie, Dan,Feng, Lingling,Peng, Hao,He, Hongwu
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p. 5804 - 5817
(2021/06/25)
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- Allylic and Allenylic Dearomatization of Indoles Promoted by Graphene Oxide by Covalent Grafting Activation Mode
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The site-selective allylative and allenylative dearomatization of indoles with alcohols was performed under carbocatalytic regime in the presence of graphene oxide (GO, 10 wt percent loading) as the promoter. Metal-free conditions, absence of stoichiometric additive, environmentally friendly conditions (H2O/CH3CN, 55 °C, 6 h), broad substrate scope (33 examples, yield up to 92 percent) and excellent site- and stereoselectivity characterize the present methodology. Moreover, a covalent activation model exerted by GO functionalities was corroborated by spectroscopic, experimental and computational evidences. Recovering and regeneration of the GO catalyst through simple acidic treatment was also documented.
- Lombardi, Lorenzo,Bellini, Daniele,Bottoni, Andrea,Calvaresi, Matteo,Monari, Magda,Kovtun, Alessandro,Palermo, Vincenzo,Melucci, Manuela,Bandini, Marco
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supporting information
p. 10427 - 10432
(2020/07/24)
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- Design, synthesis and biological evaluation of tryptamine salicylic acid derivatives as potential antitumor agents
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A series of tryptamine salicylic acid derivatives were synthesized and their antiproliferative activity against MGC-803, MCF-7, HepG2, A549 and HeLa cell lines was evaluated. The structure-activity relationship (SAR) study revealed that different substitutions of the C5 and C3′-C5′ positions have certain effects on the anti-proliferation activity. The growth assay revealed that N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide (E20) showed the most potent and broad-spectrum anticancer inhibition of all the cell lines evaluated, and was only more potent than 5-Fu for the gastric cancer cell line. Preliminary studies indicated that compound E20 could inhibit colony formation and migration of MGC-803 cells. The flow cytometry (FCM) results showed that compound E20 arrested the cell cycle in the G2/M phase and induced apoptosis of MGC-803 cells in a concentration-dependent manner. In addition, the western blot results showed that E20 can down-regulate the expression of hexokinase 2. Our studies suggest that the framework of N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide may be consider as a new type of chemical for designing effective anti-cancer drugs targeting gastric cancer cells.
- Xiong, Runde,He, Dongxiu,Deng, Xiangping,Liu, Juan,Lei, Xiaoyong,Xie, Zhizhong,Cao, Xuan,Chen, Yanming,Peng, Junmei,Tang, Guotao
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p. 573 - 583
(2019/04/30)
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- Discovery of 1,3,4-oxadiazol-2-one-containing benzamide derivatives targeting FtsZ as highly potent agents of killing a variety of MDR bacteria strains
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The spread of infections caused by multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), has created a need for new antibiotics with novel mechanisms of action. The bacterial division protein FtsZ has been identified as a novel drug target that can be exploited clinically. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents, we describe herein the design, synthesis and bioactivity of six series of novel 1,3,4-oxadiazol-2-one-containing, 1,2,4-triazol-3-one-containing and pyrazolin-5-one-containing benzamide derivatives. Among them, compound A14 was found to be the most potent antibacterial agent, much better than clinical drugs such as ciprofloxacin, linezolid and erythromycin against all the tested gram-positive strains, particularly methicillin-resistant, penicillin-resistant and clinical isolated S. aureus. Subsequent studies on biological activities and docking analyses proved that A14 functioned as an effective compound targeting FtsZ. Preliminary SAR indicated a general direction for further optimization of these novel analogues. Taken together, this research provides a promising chemotype for developing newer FtsZ-targeting bactericidal agents.
- Bi, Fangchao,Song, Di,Qin, Yinhui,Liu, Xingbang,Teng, Yuetai,Zhang, Na,Zhang, Panpan,Zhang, Nan,Ma, Shutao
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p. 3179 - 3193
(2019/06/17)
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- Synthesis of Aryl Hydrazines via CuI/BMPO Catalyzed Cross-Coupling of Aryl Halides with Hydrazine Hydrate in Water
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The N,N’-bis(2,6-dimethylphenyl)oxalamide was discovered as a powerful ligand for Cu-catalyzed cross-coupling of aryl halides with hydrazine hydrate, leading to the formation of a variety of aryl hydrazines at 80 oC in water under the assistance of K3PO4 and 4 mol% cetyltrimethylammonium bromide from aryl bromides and aryl iodides. Good to excellent yields were observed in most cases.
- Kumar, Siripuram Vijay,Ma, Dawei
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supporting information
p. 1003 - 1006
(2018/09/20)
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- Synthesis, in vitro Antimicrobial, and Cytotoxic Activities of New 1,3,4-Oxadiazin-5(6H)-one Derivatives from Dehydroabietic Acid
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A series of new 1,3,4-oxadiazin-5(6H)-one derivatives (6a–n) of dehydroabietic acid were designed and synthesized as potential antimicrobial and antitumor agents. Their structures were characterized by IR, 1H NMR, 13C NMR, MS, and elemental analyses. All the title compounds were evaluated for their antimicrobial activity against four bacterial and three fungal strains using the serial dilution method. Among them, compound 6e showed the highest antibacterial activity against Bacillus subtilis with a minimum inhibitory concentration (MIC) value of 1.9 μg/mL. In addition, the in vitro cytotoxic activities of the title compounds were also assayed against three human carcinoma cell lines (MCF-7, SMMC-7721, and HeLa) through the MTT colorimetric method. As a result, compounds 6b, 6g, 6k, and 6m exhibited significant inhibition against at least one cell line with IC50 values below 10 μM. Compound 6m was especially found to be the most potent derivative with IC50 values of 2.26 ± 0.23, 0.97 ± 0.11, and 1.89 ± 0.31 μM against MCF-7, SMMC-7721, and HeLa cells, respectively, comparable to positive control etoposide.
- Jin, Xiao-Yan,Zhang, Kang-Ping,Chen, Hao,Miao, Ting-Ting,Wang, Shi-Fa,Gu, Wen
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p. 538 - 547
(2018/06/11)
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- Synthesis and biological evaluation of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanone derivatives as tubulin inhibitors
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A series of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanones (8a-p, 9a-p) and ketoxime (10c) derivatives were designed and synthesized as antitubulin agents. All of the target compounds were evaluated for the in vitro anti-proliferative activities against three tumor cell lines (A549, HT-1080, SGC-7901). The most promising compounds in this class were (1-(p-tolyl)-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanone (9c) and its ketoxime derivative (10c), which significantly inhibited tumor cells growth with IC50 value of 0.054–0.16 μM. Meanwhile, compound 9c exhibited effectively inhibitory activity of tubulin polymerization. Consistent with its antitubulin activity, compound 9c could destructively damage microtubule network and arrest SGC-7901 cell cycle at G2/M phase significantly. The structure-activity relationship (SAR) and conformational analysis indicate that methyl group at C4-position of C-ring is critical for the activities and the amino group at the C5-position of B-ring plays a negative role in maintaining bioactivity. Furthermore, a molecular docking study was performed to elucidate its binding mode at the colchicine site in the tubulin heterodimer.
- Zhai, Min'an,Wang, Long,Liu, Shiyuan,Wang, Lijing,Yan, Peng,Wang, Junfang,Zhang, Jingbo,Guo, Haifei,Guan, Qi,Bao, Kai,Wu, Yingliang,Zhang, Weige
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p. 137 - 147
(2018/07/13)
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- Rh(II)-catalyzed intramolecular annulation of N-sulfonyl 1,2,3-triazoles with indole derivatives: A new method for synthesis pyranoindoles
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A direct and highly stereoselective approach for the synthesis of Z-alkenyl-pyranoindoles had been developed by utilizing Rh(II)-catalyzed intramolecular cyclization of N-sulfonyl-1,2,3-triazoles with indole derivatives. A variety of pyranoindoles were obtained in 44-93% yields. Moreover, a more convenient synthesis of pyranoindoles starting from terminal alkyne was realized via a Cu-Rh sequentially catalyzed one-pot cascade reaction.
- Xie, Hui,Yang, Jian-Xin,Bora, Pranjal Protim,Kang, Qiang
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supporting information
p. 3014 - 3021
(2016/05/19)
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- A diversity-oriented approach to indolocarbazoles: Via Fischer indolization and olefin metathesis: Total synthesis of tjipanazole D and i
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New synthetic strategies to indolocarbazoles have been reported via two-fold Fischer indolization under green conditions using l-(+)-tartaric acid and N,N-dimethyl urea. Starting with cyclohexanone, a bench-top starting material, this methodology has been extended to the total synthesis of natural products such as tjipanazoles D and I as well as the core structure of asteropusazole and racemosin B. Here, atom economical reactions like ring-closing metathesis, enyne-metathesis, and the Diels-Alder reaction have been used as key steps. Diverse strategies demonstrated here are useful in medicinal chemistry and materials science to design a library of decorated indoles.
- Kotha, Sambasivarao,Saifuddin, Mohammad,Aswar, Vikas R.
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supporting information
p. 9868 - 9873
(2016/10/31)
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- Design, synthesis, and biological evaluation of a series of alkoxy-3-indolylacetic acids as peroxisome proliferator-activated receptor γ/δ agonists We dedicate this article to Professor Young-Ger Suh on the occasion of his retirement.
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Abstract A series of alkoxy-3-indolylacetic acid analogs has been discovered as peroxisome proliferator-activated receptor (PPAR) agonists. Structure-activity relationship study indicated that PPARα/γ/δ activities were dependent on the nature of the hydrophobic group, the attachment position of the alkoxy linker to the indole ring, and N-alkylation of indole nitrogen. Some compounds presented significant PPARγ/δ activity and molecular modeling suggested their putative binding modes in the ligand binding domain of PPARγ. Of these, compound 51 was selected for in vivo study via an evaluation of microsomal stability in mouse and human liver. Compound 51 lowered the levels of fasting blood glucose, insulin, and HbA1c without gain in body weight in db/db mice. When compound 51 was treated, hepatic triglycerides level and the size of adipocytes in white adipose tissue of db/db mice were also reduced as opposed to treatment with rosiglitazone. Taken together, compound 51 shows high potential warranting further studies in models for diabetes and related metabolic disorders and may be in use as a chemical tool for the understanding of PPAR biology.
- Gim, Hyo Jin,Li, Hua,Jeong, Ji Hye,Lee, Su Jeong,Sung, Mi-Kyung,Song, Mi-Young,Park, Byung-Hyun,Oh, Soo Jin,Ryu, Jae-Ha,Jeon, Raok
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supporting information
p. 3322 - 3336
(2015/08/03)
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- Rhodium(III)-catalyzed in situ oxidizing directing group- assisted c-h bond activation and olefination: A route to 2-vinylanilines
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A new and efficient method for the synthesis of 2-vinylanilines from the reaction of arylhydrazine hydrochlorides with alkenes and diethyl ketone via a rhodium-catalyzed C-H activation is described. The oxidant-free olefination reaction involves the in situ generation of an -N-N=CR1R2 moiety as the oxidizing directing group thus providing an easy access to 2-vinylanilines.
- Muralirajan, Krishnamoorthy,Haridharan, Radhakrishnan,Prakash, Sekar,Cheng, Chien-Hong
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supporting information
p. 761 - 766
(2015/03/18)
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- Synthesis and biological evaluation of 3-alkyl-1,5-diaryl-1H-pyrazoles as rigid analogues of combretastatin A-4 with potent antiproliferative activity
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A series of novel 3-alkyl-1,5-diaryl-1H-pyrazoles were synthesized as combretastatin A-4 (CA-4) analogues and evaluated for antiproliferative activity against three human cancer cell lines (SGC-7901, A549 and HT-1080). Most of the target compounds displayed moderate to potent antiproliferative activity, and 7k was found to be the most potent compound. Structure-activity relationships indicated that compounds with a trimethoxyphenyl A-ring at the N-1 position of the pyrazole skeleton were more potent than those with the A-ring at the C-5 position. Tubulin polymerization and immunostaining experiments revealed that 7k potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Computational modelling demonstrated that the binding of 7k to the colchicine binding site on microtubules may involve a similar mode as CA-4.
- Xu, Qile,Qi, Huan,Sun, Maolin,Zuo, Daiying,Jiang, Xuewei,Wen, Zhiyong,Wang, Zhiwei,Wu, Yingliang,Zhang, Weige
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- Regioselective synthesis of indoles via rhodium-catalyzed C-H activation directed by an in-situ generated redox-neutral group
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A regioselective synthesis of indoles from arylhydrazine hydrochlorides with alkynes and diethyl ketone catalyzed by a rhodium complex is described. A possible mechanism involving an in-situ generated oxidizing directing group -N-Ni'CR1R2 assisted ortho-C-H activation and reductive elimination are proposed. The catalytic reaction is highly compatible with a wide range of functional arylhydrazines and alkynes. The reaction proceeds under mild reaction conditions and is atom-step economical.
- Muralirajan, Krishnamoorthy,Cheng, Chien-Hong
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p. 1571 - 1576
(2014/06/09)
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4- phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50 = 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50= 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- Indole synthesis by rhodium(III)-catalyzed hydrazine-directed C-H activation: Redox-neutral and traceless by N-N bond cleavage
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Fishing for complements! There is an alternative to the useful Fischer indole synthesis. The new method utilizes the same retrosynthetic disconnection but is based on a RhIII-catalyzed directed C-H activation step and a successive coupling with alkynes. Copyright
- Zhao, Dongbing,Shi, Zhuangzhi,Glorius, Frank
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supporting information
p. 12426 - 12429
(2013/12/04)
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- Regioselective radical arylation of anilines with arylhydrazines
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Substituted 2-aminobiphenyls have been prepared from arylhydrazines and anilines via radical arylation reactions under simple oxidative conditions. The strong directing effect of the free and unprotonated amino functionality leads to high regioselectivities, and anilines have been shown to be significantly better aryl radical acceptors than nitrobenzenes or phenyl ethers. The methodology is also applicable to phenols, which react best as phenolates under strongly basic conditions. Finally, radical arylation reactions of anilines and anilinium salts under various conditions have for the first time demonstrated that regioselectivity can also be controlled through the rearomatization step and that the addition of an aryl radical to a substituted benzene might even be reversible.
- Jasch, Hannelore,Scheumann, Julia,Heinrich, Markus R.
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p. 10699 - 10706
(2013/02/25)
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- Piecing together the puzzle: Understanding a mild, metal free reduction method for the large scale synthesis of hydrazines
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A key intermediate for the synthesis of hydrazines via a mild, metal free reduction of diazonium salts has been isolated and characterized by X-ray analysis. The presence of this intermediate is general, as demonstrated by the preparation of a number of analogues. A discussion of the mechanism and potential benefits of such a process are also described.
- Browne, Duncan L.,Baxendale, Ian R.,Ley, Steven V.
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p. 10296 - 10303
(2012/01/04)
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- Copper-mediated synthesis of substituted 2-aryl-N-benzylbenzimidazoles and 2-arylbenzoxazoles via C-H functionalization/C-N/C-O bond formation
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An efficient method for the transformation of N-benzyl bisarylhydrazones and bisaryloxime ethers to functionalized 2-aryl-N-benzylbenzimidazoles and 2-arylbenzoxazoles is described. The protocol involves a copper(II)-mediated cascade C-H functionalization/C-N/C-O bond formation under neutral conditions. Substrates having either electron-donating or -withdrawing substituents undergo the cyclization to afford the target heterocycles at moderate temperature.
- Guru, Murali Mohan,Ali, Md Ashif,Punniyamurthy, Tharmalingam
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scheme or table
p. 5295 - 5308
(2011/08/05)
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- Synthesis and antimicrobial activities of novel 1H-dibenzo[a,c]carbazoles from dehydroabietic acid
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A series of novel 1H-dibenzo[a,c]carbazole derivatives were synthesized in good yield through reaction of methyl 7-oxo-dehydroabietate with a variety of substituted phenylhydrazines. The structures of the newly synthesized compounds were confirmed by IR, 1H NMR, MS spectral studies and elemental analysis. All compounds were investigated for their activity against four bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas fluorescens) and three fungi (Trichophyton rubrum, Candida albicans and Aspergillus niger). Among the compound tested, 6d, 6e, 6f and 6m exhibited pronounced antibacterial activities and 6e and 6m also showed moderate antifungal activities. Particularly, 6d exhibited stronger antibacterial activity against B. subtilis comparable to positive control.
- Gu, Wen,Wang, Shifa
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experimental part
p. 4692 - 4696
(2010/10/03)
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- Synthesis and structure of indoline spiropyrans of the coumarin series
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New indoline spiropyrans of the coumarin series were synthesized by the condensation of indoline and hydroxyformylcoumarin derivatives. Spiropyrans, viz., derivatives of 8-formyl-7-hydroxy-4-methylcoumarin and 5-formyl-6-hydroxy-4-methylcoumarin, under irradiation are transformed into open forms, which are recyclized in the dark. The compounds formed by the condensation of the indoline derivatives with 3-formyl-4-hydroxycoumarin have an open structure of the merocyanine dyes and are transformed into spiro forms neither in the dark nor under irradiation with the visible light.
- Traven,Miroshnikov,Chibisova,Barachevsky,Venidiktova,Strokach
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p. 2417 - 2424
(2007/10/03)
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- Pyrazole derivatives
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A compound of the formula (I): wherein R1 is hydrogen or lower alkyl; R2 is lower alkyl, etc.; R3 is lower alkoxy, etc.; R4 is hydroxy, etc.; X is O, S, etc.; Y is CH or N; Z is lower alkylene or lower alkenylene; and m is 0 or 1; or salts thereof, which are useful as a medicament.
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Page/Page column 21
(2010/02/07)
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- The synthesis of phenylhydrazines from bis(2,2,2-trichloroethyl) azodicarboxylates and electron-rich arenes
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Phenylhydrazines are readily prepared in a two step sequences using electron rich arenes molecules and bis(2,2,2 trichloroethyl) azodicarboxylate (BTCEAD).
- Dufresne, Claude,Leblanc, Yves,Berthelette, Carl,McCooeye, Chris
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p. 3613 - 3624
(2007/10/03)
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- Synthesis of 1,3-dihydro-3,3-dimethyl-2H-indol-2-one derivatives as possible nonsteroidal cardiotonics
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New substituted 1,3-dihydro-3,3-dimethyl-2H-indol-2-one derivatives 19-29 and 34-43 were synthesized and examined for their inotropic activity in isolated dog ventricular tissues. Among them, compound 26 (2-(2,3-dimethoxybenzylamino)-N-(3,3,7-trimethyl-2-oxo-2,3-dihydro-1H-i ndol-5-yl)acetamide) showed very potent activity.
- Lee,Huang,Lin,Shih,Lee,Lin
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- Chemical structure and anti-inflammatory activity in the group of substituted indole-3-acetic acids
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The chemical structure of the indometacin molecule was systematically modified with the aim of producing a substance with increased anti-inflammatory activity and improved tolerance. In addition to the variations of the methylene group of the indole-3-acetic acid and substituents on the indole nucleus of indometacin, particular attention was paid to the modification of the carboxyl group of the acetic acid side chain. Among the indometacin esters, one derivative, the [1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy] acetic acid (54), showed an activity approximately twice that of indometacin in the kaolin edema test in the rat paw. Chemical modification of the new compound 54 did not further improve the activity. These studies suggest that specific substitutions on the indole nucleus, in combination with the acetic acid side chain as in 1, and especially the acetoxy acetic acid side chain in 54 are responsible for the high anti-inflammatory activity of this class of substances. Several methods for the synthesis of acemetacin are described.
- Boltze,Brendler,Jacobi,Opitz,Raddatz,Seidel,Vollbrecht
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p. 1314 - 1325
(2007/10/02)
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