New developments for the design, synthesis and biological evaluation of potent SARS-CoV 3CLpro inhibitors

Regnier, Jérémi; Sarma, Diganta; Hidaka, Kumi; Bacha, Usman; Freire, Ernesto; Hayashi, Yoshio; Kiso, Yoshiaki

doi:10.1016/j.bmcl.2009.03.118

Cited by 50 publications

(65 citation statements)

References 25 publications

(22 reference statements)

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“…The data for the compound 24a has been reported in a previous article [21]. After 1 h stirring, the Weinreb amide 23 (0.064 g, 2.0 mmol) in THF was slowly added dropwise over 20 min and then the solution was stirred for 3 h at same temperature.…”

Section: Tert-butyl ((S)-1-(benzo[d]thiazol-2-yl)-1-oxo-3-((s)-2-oxo mentioning

confidence: 97%

“…The g-lactam-thiazoles (24) were synthesized using an approach similar to the syntheses reported previously [21,22,31]. Accordingly, the optically pure L-glutamic acid ester 21 was converted to the g-lactam ester 22 by treatment with bromoacetonitrile, followed by reduction with PtO 2 (5%) and cyclization.…”

Section: Synthesismentioning

confidence: 99%

“…Recently, we performed a structureeactivity relationship study based on the lead compound, Z-Val-Leu-Ala(pyrrolidone-3-yl)-2thiazole (7) [21]. This study led to the discovery of the potent compounds 8 and 9, with K i values in the low nanomolar range [22].…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure–activity relationship study

Pillaiyar

Konno

Yamamoto

et al. 2013

European Journal of Medicinal Chemistry

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This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CL(pro). In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1' position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.

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Section: Tert-butyl ((S)-1-(benzo[d]thiazol-2-yl)-1-oxo-3-((s)-2-oxo mentioning

confidence: 97%

Section: Synthesismentioning

confidence: 99%

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Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure–activity relationship study

Pillaiyar

Konno

Yamamoto

et al. 2013

European Journal of Medicinal Chemistry

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“…Because proteolytic processing is essential for the generation of a functional replication complex, 3CL pro and PL pro are potentially effective targets for anti-SARS drugs. Most efforts reported to date have focused on the development of 3CL pro inhibitors, which have been identified in both synthetic peptidyl libraries [9][10][11] and natural derived libraries. 12,13) Fewer inhibitors of PL pro have been studied, and those that have been studied include thiopurine analogs and benzamide derivatives.…”

Section: Diarylheptanoids From Alnus Japonica Inhibit Papain-like Promentioning

confidence: 99%

Diarylheptanoids from <i>Alnus japonica</i> Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus

Park

Jeong

Kim

et al. 2012

Biological & Pharmaceutical Bulletin

165

133

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The papain-like protease (PL pro ), which controls replication of the severe acute respiratory syndrome coronavirus (SARS-CoV), has been identified as a potential drug target for the treatment of SARS. An intensive hunt for effective anti-SARS drugs has been undertaken by screening for natural product inhibitors that target SARS-CoV PL pro . In this study, diarylheptanoids 1-9 were isolated from Alnus japonica, and the inhibitory activities of these compounds against PL pro were determined. Of the isolated diarylheptanoids, hirsutenone (2) showed the most potent PL pro inhibitory activity, with an inhibitory concentration (IC 50 ) value of 4.1 µM. Structure-activity analysis showed that catechol and α,β-unsaturated carbonyl moiety in the molecule were the key requirement for SARS-CoV cysteine protease inhibition.

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“…Owing to their essential role, 3CL protease, the main protease and the PapainLike Protease (PLP2) of SARS-CoV are considered important drug targets. Based on homology modeling using crystal structures for human coronavirus and an inhibitor complex of porcine coronavirus, Anand et al (2003) proposed that rhinovirus 3C protease inhibitors might be modified for inhibiting SARS protease (Anand et al, 2003;Regnier et al, 2009). ATA is known to inhibit protein and nucleic acid interaction.…”

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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New developments for the design, synthesis and biological evaluation of potent SARS-CoV 3CLpro inhibitors

Cited by 50 publications

References 25 publications

Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure–activity relationship study

Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure–activity relationship study

Diarylheptanoids from <i>Alnus japonica</i> Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus

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

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