89001-57-0Relevant articles and documents
Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2
Welker, Armin,Kersten, Christian,Müller, Christin,Madhugiri, Ramakanth,Zimmer, Collin,Müller, Patrick,Zimmermann, Robert,Hammerschmidt, Stefan,Maus, Hannah,Ziebuhr, John,Sotriffer, Christoph,Schirmeister, Tanja
supporting information, p. 340 - 354 (2020/10/19)
Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.
Arylsulfonyl]-1H-indoles: Synthesis, SAR and biological evaluation as a novel class of 5-HT6 Receptor Antagonists
Nirogi, Ramakrishna V.S.,Badange, Rajesh Kumar,Kandukuri, Kiran Kumar,Khagga, Mukkanti
, p. 439 - 445 (2015/05/13)
In continuation to our efforts to develop better treatment options for cognitive decline, we have been focussing on 5-HT6 receptor (5-HT6R) antagonists, which are known to be involved in improving cognitive function in numerous animal models. In this paper, we report a novel series of [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1H-indole derivatives as potent and selective 5-HT6R antagonists. The lead compound from this series shows potent in vitro binding affinity, functional antagonistic activity at 5-HT6R, good pharmacokinetic profile, excellent selectivity and no Cytochrome P450 liabilities. [Figure not available: see fulltext.]
Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate
Grimster, Neil P.,Connelly, Stephen,Baranczak, Aleksandra,Dong, Jiajia,Krasnova, Larissa B.,Sharpless, K. Barry,Powers, Evan T.,Wilson, Ian A.,Kelly, Jeffery W.
supporting information, p. 5656 - 5668 (2013/06/04)
Molecules that bind selectively to a given protein and then undergo a rapid chemoselective reaction to form a covalent conjugate have utility in drug development. Herein a library of 1,3,4-oxadiazoles substituted at the 2 position with an aryl sulfonyl fluoride and at the 5 position with a substituted aryl known to have high affinity for the inner thyroxine binding subsite of transthyretin (TTR) was conceived of by structure-based design principles and was chemically synthesized. When bound in the thyroxine binding site, most of the aryl sulfonyl fluorides react rapidly and chemoselectively with the pK a-perturbed K15 residue, kinetically stabilizing TTR and thus preventing amyloid fibril formation, known to cause polyneuropathy. Conjugation t50s range from 1 to 4 min, ～1400 times faster than the hydrolysis reaction outside the thyroxine binding site. X-ray crystallography confirms the anticipated binding orientation and sheds light on the sulfonyl fluoride activation leading to the sulfonamide linkage to TTR. A few of the aryl sulfonyl fluorides efficiently form conjugates with TTR in plasma. Eleven of the TTR covalent kinetic stabilizers synthesized exhibit fluorescence upon conjugation and therefore could have imaging applications as a consequence of the environment sensitive fluorescence of the chromophore.
