35022-79-8Relevant academic research and scientific papers
Discovery of 9,10-dihydrophenanthrene derivatives as SARS-CoV-2 3CLpro inhibitors for treating COVID-19
Zhang, Jian-Wei,Xiong, Yuan,Wang, Feng,Zhang, Fu-Mao,Yang, Xiaodi,Lin, Guo-Qiang,Tian, Ping,Ge, Guangbo,Gao, Dingding
, (2021/12/09)
The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CLpro) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CLpro. The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CLpro inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CLpro inhibition activity, with IC50 values of 1.55 ± 0.21 μM and 1.81 ± 0.17 μM, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CLpro via a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CLpro inhibitor.
Novel amide and imidazole compounds as potent hematopoietic prostaglandin D2 synthase inhibitors
Olson, Kirk L.,Holt, Melissa C.,Ciske, Fred L.,Kramer, James B.,Heiple, Paige E.,Collins, Margaret L.,Johnson, Carrie M.,Ho, Chi S.,Morano, M. Ines,Barrett, Stephen D.
supporting information, (2021/01/19)
In seeking novel and potent small molecule hematopoietic prostaglandin D2 synthase (H-PGDS) inhibitors as potential therapies for PGD2-mediated diseases and conditions, we explored a series comprising multiple aryl/heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole “linker” between the pyrimidine or pyridine “core” ring and the “tail” ring system. We synthesized and screened twenty analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition assay, and a cell-based assay measuring suppression of LPS-induced PGD2 stimulation. Amide analogs show ten-fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and good in vitro metabolic stability in both human and guinea pig liver microsomes.
Ruthenium-catalysedmeta-selective CAr-H bond alkylationviaa deaminative strategy
Zhu, Ze-Fan,Chen, Guang-Le,Liu, Feng
supporting information, p. 3411 - 3414 (2021/04/07)
The use of aliphatic amines as alkylating reagents in organic synthesisviaC-N bond activation remains underdeveloped. We herein describe a novel ruthenium-catalysed and directing-group assisted protocol for the synthesis ofmeta-alkylated arenesviadual C-H and C-N activation. Bench-stable and easily handled redox-active Katritzky pyridinium salts derived from abundant amines and amino acid species were used as alkyl radical precursors. This catalytic reaction could accommodate a broad range of functional groups and provide access to variousmeta-alkylated products.
Heterocyclic and Cyclic Analogs of Propargyl-Linked Inhibitors of Dihydrofolate Reductase
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Paragraph 0087, (2015/09/22)
Compounds of Formula I and Formula IA are inhibitors of dihydrofolate reductase and are suitable for use in compositions and methods for dihydrofolate reductase inhibition or, more specifically, treatment of a fungal infection, a bacterial infection or a protozoal infection, and, in specific embodiments, treatment of a fungal infection caused by C. albicans or C. glabrata: wherein R, R1, R2, R3, R4, A, B, E, V, W, X, Y and Z are as defined herein.
Cobalt-catalyzed C-H cyanation of (Hetero)arenes and 6-Arylpurines with N -cyanosuccinimide as a new cyanating agent
Pawar, Amit B.,Chang, Sukbok
supporting information, p. 660 - 663 (2015/03/04)
A cobalt-catalyzed C-H cyanation reaction of arenes has been developed using N-cyanosuccinimide as a new electrophilic cyanating agent. The reaction proceeds with high selectivity to afford monocyanated products with excellent functional group tolerance. Substrate scope was found to be broad enough to include a wide range of heterocycles including 6-arylpurines.
Aza-annulation of enynyl azides: A new approach to substituted pyridines
Raji Reddy, Chada,Panda, Sujatarani A.,Reddy, Motatipally Damoder
, p. 896 - 899 (2015/04/13)
Synthesis of substituted pyridines through a novel aza-annulation of 2-en-4-ynyl azides, derived from MBH-acetates of acetylenic aldehydes, is described. A variety of enynyl azides having aryl, heteroaryl, and alkyl groups on the alkyne functionality successfully participated in the Ag-mediated annulation reaction to provide the corresponding 3,6-disubstituted pyridines. I2-Mediated cyclization was found to be controlled by the substituent on the alkyne functionality, which offered the 5-iodo-3,6-disubstituted pyridines from enynyl azides having an electron-rich substituent on the alkyne functionality.
Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata
G-Dayanandan, Narendran,Paulsen, Janet L.,Viswanathan, Kishore,Keshipeddy, Santosh,Lombardo, Michael N.,Zhou, Wangda,Lamb, Kristen M.,Sochia, Adrienne E.,Alverson, Jeremy B.,Priestley, Nigel D.,Wright, Dennis L.,Anderson, Amy C.
, p. 2643 - 2656 (2014/04/17)
Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 μg/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.
N -substituted hydroxylamines as synthetically versatile amino sources in the iridium-catalyzed mild C-H amidation reaction
Patel, Pitambar,Chang, Sukbok
supporting information, p. 3328 - 3331 (2014/07/08)
N-Substituted hydroxylamines such as aroyloxy- or acyloxycarbamates were successfully employed as synthetically versatile amino precursors in the iridium-catalyzed direct C-H amidation of arenes. The reaction proceeds smoothly at room temperature over a broad range of substrates with high functional group tolerance to afford N-substituted arylamine products.
Scope and limitation for FeSO4-mediated direct arylation of heteroarenes with arylboronic acids and its synthetic applications
Komeyama, Kimihiro,Nagao, Yuya,Abe, Manabu,Takaki, Ken
, p. 301 - 313 (2014/03/21)
FeSO4-mediated direct arylation of heteroarenes with arylboronic acids in the presence of K2S2O8 has been developed. A slow addition of an aqueous solution of an iron complex was crucial in the arylation. Scope and limitation of the heteroarenes and arylboronic acids are discussed. Furthermore, the direct arylation was applied to the formal total synthesis botryllazine B and sodium channel inhibitor.
Iron-mediated direct arylation with arylboronic acids through an aryl radical transfer pathway
Wang, Jian,Wang, Shan,Wang, Gao,Zhang, Ji,Yu, Xiao-Qi
supporting information, p. 11769 - 11771 (2013/01/15)
A novel iron-mediated direct C-H arylation of quinones and pyridine analogues with arylboronic acids has been developed using dichloromethane and water as solvents at ambient temperature. FeS is employed and serves as an efficient catalyst. A detailed reaction mechanism is speculated and expounded.
