63056-20-2Relevant articles and documents
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.
Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility
Ang, Chee Wei,Tan, Lendl,Sykes, Melissa L.,Abugharbiyeh, Neda,Debnath, Anjan,Reid, Janet C.,West, Nicholas P.,Avery, Vicky M.,Cooper, Matthew A.,Blaskovich, Mark A. T.
, p. 15726 - 15751 (2020/12/02)
Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.
Synthesis of biscyclometalated iridium(III) acetylacetonate complexes via a 15 min bridge-splitting reaction, their characterisations and photophysical properties
Alt?n?l?ek, Nuray,Aydemir, Murat,Tavasl?, Mustafa,Dos Santos, Paloma L.,Monkman, Andrew P.
supporting information, p. 184 - 188 (2017/10/05)
Chloro-bridged diiridium(III) complexes (4a and 4b) were subjected to a bridge-splitting reaction with acetylacetone and sodium carbonate in 2-ethoxyethanol. The reaction was complete within 15 min and two novel biscyclometalated iridium(III) acetylaceton
Contrasting Anticancer Activity of Half-Sandwich Iridium(III) Complexes Bearing Functionally Diverse 2-Phenylpyridine Ligands
Millett, Adam J.,Habtemariam, Abraha,Romero-Canelón, Isolda,Clarkson, Guy J.,Sadler, Peter J.
supporting information, p. 2683 - 2694 (2015/06/23)
We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(η5-Cp?)Ir(2-(R′-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CH2OH, -CH3) or electron-withdrawing (-F, -CHO, -NO2) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(η5-Cp?)Ir(2-(2′-fluorophenyl)pyridine)Cl] (1) and [(η5-Cp?)Ir(2-(4′-fluorophenyl)pyridine)Cl] (2) exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD+. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC50 values ranging from 1 to 89 μM, with the most potent complex, [(η5-Cp?)Ir(2-(2′-methylphenyl)pyridine)Cl] (13) (A2780 IC50 = 1.18 μM), being 10× more active than the parent, [(η5-Cp?)Ir(2-phenylpyridine)Cl], and 2× more active than [(η5-CpxPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(η5-Cp?)Ir(2-(4′-fluorophenyl)pyridine)Cl] (2) and [(η5-Cp?)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems. (Chemical Equation Presented).
Cushing's syndrome: Development of highly potent and selective CYP11B1 inhibitors of the (pyridylmethyl)pyridine type
Emmerich, Juliette,Hu, Qingzhong,Hanke, Nina,Hartmann, Rolf W.
supporting information, p. 6022 - 6032 (2013/09/02)
Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing's syndrome. Optimization of Ref 1 (5-((1H-imidazol-1- yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl) methyl)-2-phenylpyridine) with a 50-fold improved IC50 value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC 50 = 2440 nM) compared to Ref 1 (IC50 > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats.
Palladium-catalyzed cross-coupling reaction of functionalized aryl- and heteroarylbismuthanes with 2-halo(or 2-Triflyl)azines and -diazines
Petiot, Pauline,Gagnon, Alexandre
supporting information, p. 5282 - 5289 (2013/09/02)
The palladium-catalyzed cross-coupling of highly functionalized organobismuthanes with 2-halo(or 2-triflyl)pyridines, -pyrimidines, -pyrazines, and -pyridazines is reported. The reaction tolerates numerous functional groups, including aldehydes. The synthesis of a shelf-stable (formylphenyl)bismuth reagent and its use in a cross-coupling reaction is also described. The palladium-catalyzed cross-coupling of highly functionalized organobismuthanes with 2-halo(or 2-triflyl)pyridines, -pyrimidines, -pyrazines, and -pyridazines is reported. The reaction tolerates numerous functional groups, including aldehydes. The synthesis of a shelf-stable (formylphenyl)bismuth reagent and its use in cross-coupling reactions is also described. Copyright
SELECTIVE CYP11B1 INHIBITORS FOR THE TREATMENT OF CORTISOL DEPENDENT DISEASES
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Page/Page column 59, (2012/05/05)
The present invention relates to compounds which selectively inhibit CYP11B1. Preferably, the compounds of the present invention do not substantially inhibit CYP11B2. Moreover, the compounds of the present invention do not substantially inhibit CYP17 and/or CYP19, either. Amongst other applications of the compounds of the present invention, they can be used for the treatment of Cushing's syndrome or metabolic disease.
Calix[6]arene derivatives selectively functionalized at alternate sites on the smaller rim with 2-phenylpyridine and 2-fluorenylpyridine substituents to provide deep cavities
Zeng, Xianshun,Batsanov, Andrei S.,Bryce, Martin R.
, p. 9589 - 9594 (2007/10/03)
The synthesis is described of calix[6]arene derivatives 4, 9, and 14 functionalized at alternate sites on the smaller rim with 4′-(pyrid- 2″-yl)phenylmethoxy, (6′-phenylpyrid-3′-ylmethoxy), and {6′-[2-(9,9-di-n-hexylfluorenyl)]pyrid-3′-ylmethoxy} substitu
α,5-didehydro-3-picoline diradicals from skipped azaenediynes: Computational and trapping studies of an aza-Myers-Saito cyclization
Feng, Liping,Kumar, Dalip,Birney, David M.,Kerwin, Sean M.
, p. 2059 - 2062 (2007/10/03)
Equation presented. On the basis of density functional calculations, the isomerization of skipped azaenediynes (C-alkynyl-N-propargylimines) to azaenyne allenes and subsequent rapid aza-Myers-Saito cyclization to α,5-didehydro- 3-picoline were predicted. We prepared the N-propargylimine of 1-phenyl-3-tri(isopropyl)silylprop-2-yn-1-one, which undergoes proto-desilylation and isomerization to an azaenyne allene when treated with tetrabutylammonium fluoride. In the presence of 1,4-cyclohexadiene, this azaenyne allene affords 6-phenyl-3-picoline and other products corresponding to the trapping of an α,5-didehydro-3-picoline diradical.
