- Diastereospecific Synthesis of Tetrahydroisoquinolines via Radical Cyclization: Application in the Synthesis of ent-Tadalafil
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An enantioselective synthesis of 1-substituted tetrahydroisoquinolines from L–Dopa methyl ester through intramolecular aryl radical cyclization is demonstrated. The strategy consists of bromination of (S)-2-amino-3-(2-bromo-4,5-dimethoxyphenyl)propanoate followed by condensation with various aldehydes to afford bromoimidate ester. Aryl radicals generated from bromoimidate ester under the radical generating conditions (nBu3SnH/AIBN) cyclizes via 6-endo mode to afford cis-1-substituted tetrahydroisoquinolines exclusively in 99% ee. The utility of this synthetic protocol is demonstrated in the synthesis of (6S, 12aS) Tadalafil (5 steps, 21%, 99% ee). (Figure presented.).
- Barve, Indrajeet J.,Chiu, Wei-Jung,Lin, Yan-Liang,Sun, Chung-Ming
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p. 4041 - 4046
(2021/07/10)
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- A soluble iron(ii)-phthalocyanine-catalyzed intramolecular C(sp3)-H amination with alkyl azides
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Herein, we describe a soluble iron(ii)-phthalocyanine, [FeII(tBu4Pc)(py)2] (Pc = phthalocyaninato(2-)), as an effective catalyst in intramolecular C(sp3)-H bond amination, with alkyl azides as the nit
- You, Tingjie,Zeng, Si-Hao,Fan, Jianqiang,Wu, Liangliang,Kang, Fangyuan,Liu, Yungen,Che, Chi-Ming
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supporting information
p. 10711 - 10714
(2021/10/20)
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- Design, synthesis and bio-evaluation of C-1 alkylated tetrahydro-β-carboline derivatives as novel antifungal lead compounds
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The field of antifungal agent has become static and development of resistance by the pathogen as well as limited clinical efficacy of marketed drugs demand the constant development of new antifungals. The presence of hydrocarbon chain of specific length linked with various different heterocycles was found to be an important structural feature in various antifungal lead compounds. Based on the prominent antimicrobial activity of β-carboline derivatives, a set of C1 alkylated tetrahydro-β-carboline derivatives were proposed to be active against fungi. To validate and confirm the role of suitable alkyl chains linked to a β-carboline scaffold, few related analogues having C1 aryl substituents were also synthesized in one step via classic Pictet-Spengler reaction. The synthesized library was evaluated for its antifungal activity against C. albicans, C. krusei, C. parapsilosis, C. kefyr, C. glabrata, C. tropicalis and C. neoformans. One of the library members (compound 12c), with n-alkyl chain of eight carbons exhibited potent antifungal activity against C. glabrata and C. kefyr. The lead compound, being selectively toxic also demonstrated prominent synergy enhancing the potency of antifungal drugs up to 10-fold. The time kill kinetic studies confirmed the efficacy of compound 12c, where the results obtained were comparable to that of Amp B. FE-SEM analysis revealed the increased asymmetry, disintegration and roughness of cell surface which could be because of the possible interaction of compound 12c at membrane level or interference in cell wall structure. Apoptosis/necrosis detection assay confirmed the significant apoptotic activity in C. glabrata cells after 12c treatment which was responsible for the rapid killing of C. glabrata cells.
- Singh, Rahul,Jaisingh, Aanchal,Maurya, Indresh K.,Salunke, Deepak B.
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supporting information
(2019/12/27)
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- Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease
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Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.
- Mao, Fei,Wang, Huan,Ni, Wei,Zheng, Xinyu,Wang, Manjiong,Bao, Keting,Ling, Dazheng,Li, Xiaokang,Xu, Yixiang,Zhang, Haiyan,Li, Jian
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p. 328 - 345
(2018/03/01)
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- 3,4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof
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The present invention relates to a 3,4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof, and specifically discloses a compound represented by a formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each group is defined in the specification. According to the present invention, the compound has dual inhibitory activity on acetylcholinesterase and phosphodiesterase 5, and has good blood-brain barrier permeability, such that the compound can be used for preparing drugs for treatment and/or prevention ofAlzheimer's diseases. The formula I is defined in the specification.
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Paragraph 0113; 0115; 0116; 0117
(2018/09/11)
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- Synthesis of tadalafil (Cialis) from l-tryptophan
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The first synthesis of tadalafil 1 (Cialis) from l-tryptophan is described. The title compound 1 was synthesized via seven steps from l-tryptophan methyl ester hydrochloride in 42.3% overall yield. Two characteristic steps involved in this synthesis are t
- Xiao, Sen,Shi, Xiao-Xin,Xing, Jing,Yan, Jing-Jing,Liu, Shi-Ling,Lu, Wei-Dong
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experimental part
p. 2090 - 2096
(2010/03/04)
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- Conversion of tryptophan into ?-carboline derivatives
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The invention belongs in the field of organic chemistry and relates to a new shortened Pictet-Spengler type reaction for preparing isomerically pure β-carboline compounds useful for the synthesis of tadalafil.
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Page/Page column 9
(2009/10/18)
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- The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1′,2′ :1,6]pyrido[3,4-b]indole-1,4-dione analogues
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Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
- Daugan, Alain,Grondin, Pascal,Ruault, Cécile,Le Monnier de Gouville, Anne-Charlotte,Coste, Hervé,Linget, Jean Michel,Kirilovsky, Jorge,Hyafil, Fran?ois,Labaudinièret, Richard
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p. 4533 - 4542
(2007/10/03)
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