17536-38-8Relevant academic research and scientific papers
Indole compounds with: N-ethyl morpholine moieties as CB2 receptor agonists for anti-inflammatory management of pain: Synthesis and biological evaluation
Ji, Jing,Li, Jiaojiao,Li, Zhengfu,Xu, Ruibo
, p. 1935 - 1947 (2019)
The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with N-ethyl morpholine moieties (compounds 1-56) were designed, synthesized and biologically evaluated. Compounds 1, 2, 3, 46 and 53 exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC50(CB1)/EC50(CB2) greater than 1000). The most active compound, compound 2, was more potent than the standard drug GW405833 for in vitro agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, compound 2 had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1 h time point, compound 2 had a dose-dependent reversal for hyperalgesia with an estimated ED50 value of 1.097 mg kg-1. Moreover, compound 2 significantly suppressed the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound 2 on inflammatory pain were superior to those of GW405833, suggesting that compound 2 may be a promising therapeutic drug that needs further validation.
One-Pot Synthesis of Indoles and Pyrazoles via Pd-Catalyzed Couplings/Cyclizations Enabled by Aqueous Micellar Catalysis
Akporji, Nnamdi,Braga, Felipe C.,Gabriel, Christopher M.,Landstrom, Evan B.,Lee, Nicholas R.,Lipshutz, Bruce H.
supporting information, (2020/09/02)
An effective one-pot synthesis of either indoles or pyrazoles can be achieved via Pd-catalyzed aminations followed by subsequent cyclizations facilitated by aqueous micellar catalysis. This new technology includes efficient couplings with low loadings of palladium, a more stable source of the required hydrazine moiety, greater atom economy for the initial coupling, and reduced reaction temperatures, all leading to environmentally responsible processes.
Myoglobin-Catalyzed C?H Functionalization of Unprotected Indoles
Vargas, David A.,Tinoco, Antonio,Tyagi, Vikas,Fasan, Rudi
supporting information, p. 9911 - 9915 (2018/07/31)
Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal-catalyzed carbene transfer has provided an attractive route to afford C3-functionalized indoles, these protocols are viable only in the presence of N-protected indoles, owing to competition from the more facile N?H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C?H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α-diazoacetate to give the corresponding C3-functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti-inflammatory drug indomethacin.
Synthesis of Functionalized Indoles via Palladium-Catalyzed Aerobic Cycloisomerization of o-Allylanilines Using Organic Redox Cocatalyst
Ning, Xiao-Shan,Wang, Mei-Mei,Qu, Jian-Ping,Kang, Yan-Biao
, p. 13523 - 13529 (2018/10/25)
A scalable and practical synthesis of functionalized indoles via Pd-tBuONO cocatalyzed aerobic cycloisomerization of o-allylanilines is reported. Using molecular oxygen as a terminal oxidant, a series of substituted indoles were prepared in moderate to good yields. The avoidance of hazardous oxidants, heavy-metal cocatalysts, and high boiling point solvents such as DMF and DMSO enables this method to be applied in pharmaceutical synthesis. A practical gram-scale synthesis of indomethacin demonstrates its application potential.
Pd-tBuONO Cocatalyzed Aerobic Indole Synthesis
Ning, Xiao-Shan,Liang, Xin,Hu, Kang-Fei,Yao, Chuan-Zhi,Qu, Jian-Ping,Kang, Yan-Biao
, p. 1590 - 1594 (2018/04/30)
A Pd-tBuONO co-catalyzed scalable and practical synthesis of indoles with molecular oxygen as terminal oxidant is developed. Either terminal or internal 2-vinylanilines could be smoothly converted to desired indoles under one general condition. This method has been evaluated in the large scale synthesis of indomethacin and a potential anti-breast cancer drug candidate 1. (Figure presented.).
Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study
Lepri, Susan,Buonerba, Federica,Goracci, Laura,Velilla, Irene,Ruzziconi, Renzo,Schindler, Bryan D.,Seo, Susan M.,Kaatz, Glenn W.,Cruciani, Gabriele
, p. 867 - 891 (2016/02/23)
Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 μM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported.
Synthesis of indoles through Rh(III)-catalyzed C-H cross-coupling with allyl carbonates
Gong, Tian-Jun,Cheng, Wan-Min,Su, Wei,Xiao, Bin,Fu, Yao
, p. 1859 - 1862 (2014/03/21)
A practical Rh-catalyzed reaction was developed to achieve 2-alkyl-substituted indole synthesis. The reaction can tolerate a variety of synthetically important functional groups. The indole products can also be transformed into other important skeletons. Two bioactive compounds, that is indomethacin and pravadoline were prepared using the new method.
Efficient preparation of polyfunctional indoles via a zinc organometallic variation of the Fischer indole synthesis
Zhang, Zhi-Guang,Haag, Benjamin A.,Li, Jin-Shan,Knochel, Paul
experimental part, p. 23 - 29 (2011/02/26)
Functionalized organozinc reagents readily react with various aryldiazonium salts furnishing regioselectively polyfunctional indoles after heating with microwave irradiation. This new organometallic variation of the Fischer indole synthesis tolerates a wide range of functional groups and can be readily scaled up. Georg Thieme Verlag Stuttgart · New York.
Fischer indole synthesis with organozinc reagents
Haag, Benjamin A.,Zhang, Zhi-Guang,Li, Jin-Shan,Knochel, Paul
supporting information; experimental part, p. 9513 - 9516 (2011/02/24)
Updated classic: Primary and secondary alkylzinc reagents add to various aryldiazonium salts leading regioselectively to polyfunctional indoles by means of a [3,3]-sigmatropic shift and subsequent aromatization. This organometallic variation of the Fischer indole synthesis tolerates a wide range of functional groups and displays absolute regioselectivity. Copyright
Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors
Wey, Shiow-Jyi,Augustyniak, Michael E.,Cochran, Edward D.,Ellis, James L.,Fang, Xinqin,Garvey, David S.,Janero, David R.,Letts, L. Gordon,Martino, Allison M.,Melim, Terry L.,Murty, Madhavi G.,Richardson, Steward K.,Schroeder, Joseph D.,Selig, William M.,Trocha, A. Mark,Wexler, Roseanne S.,Young, Delano V.,Zemtseva, Irina S.,Zifcak, Brian M.
, p. 6367 - 6382 (2008/03/27)
Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.
