Design, Synthesis, and Evaluation of Inhibitors for Severe Acute Respiratory Syndrome 3C-Like Protease Based on Phthalhydrazide Ketones or Heteroaromatic Esters

Zhang, Jianmin; Pettersson, Hanna; Huitema, Carly; Niu, Cuijuan; Jiang, Yin; James, Michael N.G.; Eltis, Lindsay D.; Vederas, John C.

doi:10.1021/jm061425k

Cited by 77 publications

(71 citation statements)

References 34 publications

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“…A shift of approximately 217 Da was observed after treatment of SARS-CoV 3CLpro with the inhibitor confirming covalent modification. Covalent modification by similar reactive esters has also been reported 13a,20.…”

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confidence: 57%

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Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors

Ghosh

Gong

Grum-Tokars

et al. 2008

Bioorganic & Medicinal Chemistry Letters

105

136

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Design, synthesis and biological evaluation of a series of 5-chloropyridine ester-derived severe acute respiratory syndrome-coronavirus chymotrypsin-like protease inhibitors is described. Position of the carboxylate functionality is critical to potency. Inhibitor 10 with a 5-chloropyridinyl ester at position 4 of the indole ring is the most potent inhibitor with a SARS 3Clpro IC 50 value of 30 nM and antiviral EC 50 value of 6.9 μM. Molecular Docking studies have provided possible binding modes of these inhibitors.© 2008 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 4 While SARS is contained in the world and no more cases have been reported since April 2004, there is expectation that this epidemic will strike again in an even more severe form. Furthermore, the nature of its unpredictable outbreak is a potential threat to the global economy and public heath. To date, no effective therapy exists for this viral illness. NIH Public AccessThe SARS coronavirus is a positive-strand RNA virus. The 5′ two-thirds of the genome encodes two overlapping polyproteins, pp1a and pp1ab, which are processed to generate the viral replication complex. During viral replication, the replicase polyprotein undergoes extensive processing by two viral proteases namely, chymotrypsin-like protease (3CLpro) and papainlike protease (PLpro). 5,6 Because of their essential roles in viral replication, both proteases are recognized as attractive targets for development of anti-SARS therapeutics. 7 The structure and activity of active sites of both SARS-CoV 3CLpro and SARS-CoV PLpro have been elucidated. Thus far, inhibitor design efforts are mostly limited to SARS-CoV 3CLpro and numerous covalent and noncovalent inhibitors have been reported. 7 In our continuing interest in the design and development of SARS-CoV 3CLpro inhibitors, we recently reported structurebased design of a number of potent peptidomimetic SARS-CoV 3CLpro inhibitors (1 and 2). The SARS-CoV 3CLpro active site contains a catalytic dyad where a cysteine residue acts as a nucleophile and a histidine residue acts as the general acid base. 9 The inhibitors bind to SARS-CoV-3CLpro through covalent bonding with the active site cysteine 145 residue. These inhibitors contain peptidomimetic scaffolds and lacked adequate potency, particularly antiviral activity suitable for drug-development. Recently, Wong and co-workers reported a new class of potent small molecule benzotriazole ester-based 3CLpro inhibitors. Compound 3 is the most potent inhibitor among the benzotriazole esters. 10 The mode of acti...

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confidence: 57%

“…It seems the indole-5-carboxylate moiety plays an important role in binding with the enzyme active site. Another class of hetereoaromatic ester inhibitors was also identified and studied 12, 13. The 5-chloropyridine moiety in 4 proved to be the key unit for the activity against 3CLpro.…”

mentioning

confidence: 99%

Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors

Ghosh

Gong

Grum-Tokars

et al. 2008

Bioorganic & Medicinal Chemistry Letters

105

136

View full text Add to dashboard Cite

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“…Virtual screening (Plewczynski et al, 2007;Mukherjee et al, 2008;Nguyen et al, 2011) or a high-throughput screening of small molecule libraries have identified inhibitorsincluding an anti-HIV agent and serotonin antagonist, cinanserin (Blanchard et al, 2004;Kao et al, 2004;Wu et al, 2004a;Chen et al, 2005). Other 3CL protease inhibitors identified so far belongto categories such as plant derived phenolic or flavonoid compounds (Lin et al, 2005;Nguyen et al, 2012), active site, nonactive site or competitive inhibitors (Kaeppler et al, 2005;Lee et al, 2005;Du et al, 2007;Ryu et al, 2010), ketones or ester based inhibitors (Goetz et al, 2007;Zhang et al, 2007;Ghosh et al, 2008;Shao et al, 2008;Verschueren et al, 2008;Zhang et al, 2008), modified peptidomimetic inhibitors (Ghosh et al, 2007), metal conjugated inhibitors (Lee et al, 2007;…”

Section: Viral Protease Inhibitorsmentioning

confidence: 99%

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

Bhardwaj¹

2013

American Journal of Virology

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No non-human reservoirs for smallpox-and polio-viruses has contributed to the success of worldwide eradication of smallpox and a significant control of poliomyelitis. Most emerging and re-emerging viruses including SARS Coronavirus (SARS-CoV), have animal reservoirs and therefore,they impose a constant threat of host jump leading tooutbreaksin humans. It is desirable to be ready for control of infections that are caused by zoonotic pathogens, even after an outbreak has ended. This literature review is a compilation of advances made so far for diagnosis and treatment of SARS.

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“…1,4,8,11- temperature for ca. 18 h. The solvent was evaporated to give a yellow solid which was used without further purification [29]. To a solution of XX (Scheme 2) [30] (80 mg, 0.14 mmol) in DMF (5 mL) was added 1H-pyrrole-2-carbonyl chloride (18.3 mg, 0.14 mmol) and the mixture stirred at room temperature until no starting materials could be detected by LC-MS and a molecular ion consistent with the desired monosubstituted product was observed (ca.…”

Section: Reagentsmentioning

confidence: 99%

Inducing Sensitivity to Heavy Metal Ions in Polypyrrole Modified by Azamacrocyclic Ligands

et al. 2009

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An azamacrocyle doped polypyrrole is considered as a material showing heavy metal cation sensitivity and examples with Ni 2þ , Zn 2þ , and Cu 2þ cations are tested. Heavy metal ion binding agent: 1,4,8,11-tetraazacyclotetradecane (cyclam) or its derivatives were introduced into a conducting polymer film in different ways: i) neutral cyclam was incorporated by polymerization from 1,4,8,11-tetraazacyclotetradecane containing solution, ii) 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetate anions (TETA) were introduced, acting as co-dopant ions in chloride containing solutions, iii) polymerization was carried out from solution containing pyrrole and a composite of pyrrole with Ni(II) cyclam derivative complex: N-(4-amino-6-(1,3,5,8,12-pentaazacyclotetradecan-3-yl)-1,3,5-triazin-2-yl)-1H-pyrrole-2-carboxamide nickel(II) perchlorate (ET679). In KCl and NiCl 2 solutions the freshly obtained oxidized polypyrrole layers modified by cyclam or TETA anions exhibited typical anion exchanging properties as confirmed in voltammetric and potentiometric experiments. Potentiometric cationic sensitivity and selectivity towards nickel ions was induced after conditioning or polarization in alkaline (NaOH or KOH) media and Ni 2þ solution; this was accompanied by Ni(II) retention in the polymer film. Similar cationic sensitivity was observed also for polypyrrole with cyclam in case of Zn 2þ and Cu 2þ ions. For copolymers of pyrrole with ET679 significant potentiometric cationic sensitivity to Ni 2þ , Zn 2þ and Cu 2þ was recorded even for freshly prepared layers, pointing to surface exposed heavy metal cation binding properties of the macrocylic ligand covalently built into the film.

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Design, Synthesis, and Evaluation of Inhibitors for Severe Acute Respiratory Syndrome 3C-Like Protease Based on Phthalhydrazide Ketones or Heteroaromatic Esters

Cited by 77 publications

References 34 publications

Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors

Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

Inducing Sensitivity to Heavy Metal Ions in Polypyrrole Modified by Azamacrocyclic Ligands

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