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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Non-covalent triazole-based inhibitors of the SARS main proteinase 3CLpro - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Non-covalent triazole-based inhibitors of the SARS main proteinase 3CLpro">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2013/03/14">
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<meta name="citation_author" content="Mark Turlington">
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<meta name="citation_author" content="Aspen Chun">
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<meta name="citation_author" content="Jon Jacobs">
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<meta name="citation_author" content="Eric Dawson">
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<meta name="citation_author" content="J. Scott Daniels">
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<meta name="citation_author" content="Adrian Saldanha">
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<meta name="citation_author" content="Peter Chase">
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<meta name="citation_author" content="Peter Hodder">
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<meta name="citation_author" content="Aimee Eggler">
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<meta name="citation_author" content="Valerie Tokars">
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<meta name="citation_author" content="Andrew Mesecar">
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<meta name="citation_author" content="Craig W. Lindsley">
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<meta name="citation_author" content="Shaun R. Stauffer">
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<meta name="citation_pmid" content="23762941">
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<meta name="DC.Title" content="Non-covalent triazole-based inhibitors of the SARS main proteinase 3CLpro">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Mark Turlington">
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<meta name="DC.Contributor" content="Aspen Chun">
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<meta name="DC.Contributor" content="Jon Jacobs">
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<meta name="DC.Contributor" content="Eric Dawson">
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<meta name="DC.Contributor" content="J. Scott Daniels">
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<meta name="DC.Contributor" content="Adrian Saldanha">
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<meta name="DC.Contributor" content="Peter Chase">
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<meta name="DC.Contributor" content="Peter Hodder">
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<meta name="DC.Contributor" content="Aimee Eggler">
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<meta name="DC.Contributor" content="Valerie Tokars">
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<meta name="DC.Contributor" content="Andrew Mesecar">
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<meta name="DC.Contributor" content="Craig W. Lindsley">
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<meta name="DC.Contributor" content="Shaun R. Stauffer">
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<meta name="DC.Date" content="2013/03/14">
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<meta name="description" content="ML300 (CID 46861530) is being declared as a new first in class 3CLpro probe inhibitor. ML300 belongs to a new series of triazole-based SARS main proteinase 3CLpro inhibitors that follow our first dipeptide probe ML188. Based upon X-ray crystal data from a related inhibitor, ML300 is believed to interact within the 3CLpro enzyme active site via a novel binding mode distinct from both our first probe ML188 and other known peptidomimetic inhibitors. Relative to ML188 and based upon X-ray crystal data, the MW of the triazole series described here can be reduced resulting in truncation to a single backbone amide. Structure-activity relationships taking into account ligand efficiency and studies leading to the identification of ML300 will be described. ML300 should allow others in the field to access a novel non-covalent starting point for 3CLpro inhibitor design and optimization.">
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<meta name="og:description" content="ML300 (CID 46861530) is being declared as a new first in class 3CLpro probe inhibitor. ML300 belongs to a new series of triazole-based SARS main proteinase 3CLpro inhibitors that follow our first dipeptide probe ML188. Based upon X-ray crystal data from a related inhibitor, ML300 is believed to interact within the 3CLpro enzyme active site via a novel binding mode distinct from both our first probe ML188 and other known peptidomimetic inhibitors. Relative to ML188 and based upon X-ray crystal data, the MW of the triazole series described here can be reduced resulting in truncation to a single backbone amide. Structure-activity relationships taking into account ligand efficiency and studies leading to the identification of ML300 will be described. ML300 should allow others in the field to access a novel non-covalent starting point for 3CLpro inhibitor design and optimization.">
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match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK143547_"><span class="title" itemprop="name">Non-covalent triazole-based inhibitors of the SARS main proteinase 3CLpro</span></h1><p class="contribs">Turlington M, Chun A, Jacobs J, et al.</p><p class="fm-aai"><a href="#_NBK143547_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p><a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> (CID 46861530) is being declared as a new first in class 3CLpro probe inhibitor. <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> belongs to a new series of triazole-based SARS main proteinase 3CLpro inhibitors that follow our first dipeptide probe <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a>. Based upon X-ray crystal data from a related inhibitor, <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> is believed to interact within the 3CLpro enzyme active site via a novel binding mode distinct from both our first probe <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a> and other known peptidomimetic inhibitors. Relative to <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a> and based upon X-ray crystal data, the MW of the triazole series described here can be reduced resulting in truncation to a single backbone amide. Structure-activity relationships taking into account ligand efficiency and studies leading to the identification of <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> will be described. <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> should allow others in the field to access a novel non-covalent starting point for 3CLpro inhibitor design and optimization.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> <a href="/nuccore/1365502107" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">MH084162</a></p><p><b>Screening Center Name & PI:</b> Scripps Research Institute Molecular Screening Center, Hugh Rosen</p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> Andrew Mesecar, Purdue University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1859" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1859</a></p><div id="ml300.s1"><h2 id="_ml300_s1_">Probe Structure & Characteristics</h2><div id="ml300.fu1" class="figure"><div class="graphic"><img src="/books/NBK143547/bin/ml300fu1.jpg" alt="Image ml300fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml300tu1"><a href="/books/NBK143547/table/ml300.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml300tu1" rid-ob="figobml300tu1"><img class="small-thumb" src="/books/NBK143547/table/ml300.tu1/?report=thumb" src-large="/books/NBK143547/table/ml300.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml300.tu1"><a href="/books/NBK143547/table/ml300.tu1/?report=objectonly" target="object" rid-ob="figobml300tu1">Table</a></h4></div></div></div><div id="ml300.s2"><h2 id="_ml300_s2_">1. Recommendations for Scientific Use of the Probe</h2><p>This probe (<a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a>, CID 46861530) represents a second class of non-covalent small molecule inhibitors of the SARS main proteinase 3CLpro using a simple dipeptide backbone. This probe possesses excellent selectivity versus a large panel of GPCRs, ion channels and transporters. In addition, based upon X-ray crystallography data of 3CLpro bound inhibitor <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24808289" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 24808289</a> from the <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> series, this probe displays a novel mode of inhibition at the active site distinct from our previous probe <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a>. As a result of the unique interaction and SAR observed against 3CLpro by <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> within this triazole, a unique opportunity to identify potent inhibitors of 3CLpro and potentially related PL enzymes from other coronavirus strains exists. To date, the coronavirus 3CL/PL field has been limited by probes which are high MW peptidomimetics with weak inhibition of 3CLpro and/or probes containing reactive covalent modifier groups. <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> does not contain any apparent reactive functional groups and contains only one backbone amide, an improvement over the initial triazole lead <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24808289" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 24808289</a>, which contains two backbone amides occupying four residue pockets of the enzyme. Further, cellular studies using <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> will provide insight into their potential relative to existing tool compounds including <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a>.</p><p>In addition to structural insights provided by <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a>, we believe the SAR and structure details provided by the <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> analog <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24808289" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 24808289</a> will provide a means upon which to facilitate rapid structure-based inhibitor optimization. In addition, this probe will be of use in examining its activity against other emerging CoV strains expressing 3CLpro. This includes the recently identified SAR-like virus called HCoV-EMC, which has been shown to be lethal in the few cases reported to date.</p></div><div id="ml300.s3"><h2 id="_ml300_s3_">2. Materials and Methods</h2><div id="ml300.s4"><h3>2.1. Assays</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml300tu2"><a href="/books/NBK143547/table/ml300.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml300tu2" rid-ob="figobml300tu2"><img class="small-thumb" src="/books/NBK143547/table/ml300.tu2/?report=thumb" src-large="/books/NBK143547/table/ml300.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml300.tu2"><a href="/books/NBK143547/table/ml300.tu2/?report=objectonly" target="object" rid-ob="figobml300tu2">Table</a></h4></div></div></div><div id="ml300.s5"><h3>2.2. Probe Chemical Characterization</h3><p>Probe compound <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> was prepared according to the scheme in <a class="figpopup" href="/books/NBK143547/figure/ml300.f1/?report=objectonly" target="object" rid-figpopup="figml300f1" rid-ob="figobml300f1">Figure 1</a> and provided the following characterization data: LC-MS (>98%) <i>m/z</i> = 432.1 [M+H]; <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.05 (1H, s), 8.02 (1H, d, J = 8.4 Hz), 7.61 (2H, d, <i>J</i> = 8.6 Hz), 7.49 (2H, m), 7.36 (1H, p, J = 4.2 Hz), 7.23 (1H, m), 7.02 (3H, m), 6.95 (1H, d, <i>J</i> = 4.92 Hz), 5.15 (2H, s), 4.84 (2H, s), 1.55 (1H, m), 1.09 (2H, m), 0.85 (2H, m); <sup>13</sup>C NMR (100 MHz, CDCl<sub>3</sub>) δ 172.6, 164.9, 145.7, 139.3, 136.7, 134.9, 133.7, 128.7, 128.1, 127.8, 126.2, 124.4, 124.1, 120.9, 119.7, 109.8, 49.7, 48.4, 15.5, 8.2; HRMS (ESI) m/z 432.1497 ([M+H]<sup>+</sup>, 100%) calcd for C<sub>23</sub>H<sub>22</sub>N<sub>5</sub>O<sub>2</sub>S, 432.1494.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml300f1" co-legend-rid="figlgndml300f1"><a href="/books/NBK143547/figure/ml300.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml300f1" rid-ob="figobml300f1"><img class="small-thumb" src="/books/NBK143547/bin/ml300f1.gif" src-large="/books/NBK143547/bin/ml300f1.jpg" alt="Figure 1. Synthetic procedure and spectral data for ML300 (CID 46861530)." /></a><div class="icnblk_cntnt" id="figlgndml300f1"><h4 id="ml300.f1"><a href="/books/NBK143547/figure/ml300.f1/?report=objectonly" target="object" rid-ob="figobml300f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Synthetic procedure and spectral data for ML300 (CID 46861530). </p></div></div><p><b>Solubility.</b> Solubility in PBS at pH 7.4 was determined to be 29 μM or 13 μg/mL. <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> shows good solubility up >100 μM DMSO and up to 40 mM DMSO which is currently used for original stocks of novel compounds shipped to the assay provider for testing. In addition, solubility in organic solvents for <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> versus <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a> appears to be improved.</p><p><b>Stability.</b> Stability was determined for <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> in PBS buffer at room temperature with both 5 and 10% DMSO. <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a> was found to be completely stable (>99% intact) after 48h.</p><p><b>Compounds added to the SMR collection (MLS#s):</b> MLS004084528 (<a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a>, CID 46861530, 20.4 mg); MLS004084529 (CID 46861523, 8.8 mg); MLS004084530 (CID 45382022, 5.5 mg); MLS004084531 (CID 45382030, 7.4 mg); MLS004084532 (CID 46861528, 16.1 mg); MLS004084533 (CID 46861529, 17.6 mg).</p></div><div id="ml300.s6"><h3>2.3. Probe Preparation</h3><div id="ml300.s7"><h4>N-(4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(thiophen-3- ylmethyl)acetamido)phenyl)cyclopropanecarboxamide (ML300, CID 46861530)</h4><div id="ml300.fu2" class="figure"><div class="graphic"><img src="/books/NBK143547/bin/ml300fu2.jpg" alt="Image ml300fu2" /></div></div><p><b>Step 1: Preparation of tert-butyl (4-((thiophen-3-ylmethyl)amino)phenyl)carbamate.</b> 3-thiophenecarboxylic acid (0.383 mL, 4.4 mmol, 1.0 equiv) and N-Boc-p-phenylenediamine (1.12 g, 5.4 mmol, 1.22 equiv) were dissolved in dichloroethane (44 mL, 0.1 M) in a 100 mL round bottom flask. Sodium triacetoxyborohydride (1.43 g, 6.7 mmol, 1.52 equiv) was added and the reaction was stirred at room temperature for 1 h. The reaction was determined to be complete by LC-MS, quenched with NH<sub>4</sub>Cl (sat’d, aqueous), and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over MgSO<sub>4</sub>, concentrated, and purified by silica gel column chromatography, eluting with EtOAc/hexanes. The title compound eluted at 35% EtOAc/hexanes and was isolated as a light yellow solid in quantitative yield (1.34 g). LC-MS (>98%) <i>m/z</i> = 305.2 [M+H].</p><div id="ml300.fu3" class="figure"><div class="graphic"><img src="/books/NBK143547/bin/ml300fu3.jpg" alt="Image ml300fu3" /></div></div><p><b>Step 2: Preparation of tert-butyl (4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(thiophen-3-ylmethyl)acetamido)phenyl)carbamate.</b><i>Tert</i>-butyl (4-((thiophen-3-ylmethyl)amino)phenyl)carbamate (1.1 g, 3.6 mmol, 1.0 equiv) and HATU (1.71 g, 4.5 mmol, 1.25 equiv) were combined in DMF (30 mL, 0.12 M) in a 100 mL round bottom flask. <i>N</i>,<i>N</i>-diisopropylethylamine (1.56 mL, 9 mmol, 2.5 equiv) was added and the reaction was stirred at room temperature for 10 min. 1-Benzotriazolylacetic acid (736 mg, 4.16, 1.15 equiv) was added and the reaction was stirred at room temperature for 16 h after which no further formation of the product was observed by LC-MS. The mixture was diluted with EtOAc (100 mL) and the organic layer was washed with water (3 × 25 mL). The organic layer was dried over MgSO<sub>4,</sub> concentrated under reduced pressure, and purified by silica gel column chromatography eluting with EtOAc/hexanes. The title compound eluted at 50% EtOAc/hexanes and was isolated as an off-white solid in 56% yield (931 mg). LC-MS (>98%) <i>m/z</i> = 464.2 [M+H].</p><div id="ml300.fu4" class="figure"><div class="graphic"><img src="/books/NBK143547/bin/ml300fu4.jpg" alt="Image ml300fu4" /></div></div><p><b>Step 3: Preparation of N-(4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(thiophen-3-ylmethyl)acetamido)phenyl)cyclopropanecarboxamide.</b><i>Tert</i>-butyl (4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(thiophen-3-ylmethyl)acetamido)phenyl)carbamate (920 mg, 1.98 mmol, 1.0 equiv) was dissolved in CH<sub>2</sub>Cl<sub>2</sub> (3 mL, 0.66 M) in a 20 mL scintillation vial. Trifluoroacetic acid (TFA, 2 mL, 26.1 mmol, 13 equiv) was added, and after stirring at room temperature for 1 h the starting material was determined to be consumed by LC-MS. The solvents were evaporated under reduced pressure and the resulting de-Boc protected aniline was used without purification. LC-MS (>98%) <i>m/z</i> = 364.1 [M+H].</p><p>The aniline (1.98 mmol, 1.0 equiv) was re-dissolved in CH<sub>2</sub>Cl<sub>2</sub> (20 mL, 0.1 M) and Et<sub>3</sub>N (2.48 mL, 17.82 mmol, 9 equiv) was added. (Excess Et<sub>3</sub>N was used to neutralize any residual TFA, and the reaction mixture was determined to be basic by checking with pH paper.) Cyclopropanecarbonyl chloride (0.23 mL, 2.48, 1.25 equiv) was added and the reaction mixture was stirred for 1 h, after which the starting material was determined to be consumed by LC-MS. The reaction was quenched with NH<sub>4</sub>Cl (sat’d aqueous) and extracted with CH<sub>2</sub>Cl<sub>2</sub> (3 × 20 mL). The combined organic layers were dried over MgSO<sub>4</sub>, concentrated, and purified by silica gel column chromatography eluting with EtOAc\hexanes. The title compound eluted at 75% EtOAc/hexanes to yield a tan solid in 39% yield (330 mg). LC-MS (>98%) <i>m/z</i> = 432.1 [M+H]; <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.05 (1H, s), 8.02 (1H, d, J = 8.4 Hz), 7.61 (2H, d, <i>J</i> = 8.6 Hz), 7.49 (2H, m), 7.36 (1H, p, J = 4.2 Hz), 7.23 (1H, m), 7.02 (3H, m), 6.95 (1H, d, <i>J</i> = 4.92 Hz), 5.15 ( 2H, s), 4.84 (2H, s), 1.55 (1H, m), 1.09 (2H, m), 0.85 (2H, m); <sup>13</sup>C NMR (100 MHz, CDCl<sub>3</sub>) δ 172.6, 164.9, 145.7, 139.3, 136.7, 134.9, 133.7, 128.7, 128.1, 127.8, 126.2, 124.4, 124.1, 120.9, 119.7, 109.8, 49.7, 48.4, 15.5, 8.2; HRMS (ESI) m/z 432.1497 ([M+H]<sup>+</sup>, 100%) calcd for C<sub>23</sub>H<sub>22</sub>N<sub>5</sub>O<sub>2</sub>S, 432.1494.</p></div></div></div><div id="ml300.s8"><h2 id="_ml300_s8_">3. Results</h2><div id="ml300.s9"><h3>3.1. Dose Response Curves for Probe</h3><div id="ml300.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143547/bin/ml300f2.jpg" alt="Figure 2. M-M Inhibition Curve for ML300." /></div><h3><span class="label">Figure 2</span><span class="title">M-M Inhibition Curve for ML300</span></h3></div></div><div id="ml300.s10"><h3>3.2. Cellular Activity</h3><p>Cellar activity measurements are still in progress using against SARS-CoV Urbani infected Vero E6 cells using <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a>. Prior studies using <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a> suggest cellular activity above 10 micromolar is likely for <a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a>. Although it remains to be seen, based on the EC<sub>50</sub>/IC<sub>50</sub> ratio observed for <a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a> (<10) as a minimum, we expect improvements in potency below micromolar level will be required to achieve good cellular activity for the triazole series below 10 μM.</p></div><div id="ml300.s11"><h3>3.3. Profiling Assays</h3><p>The probe molecule (<a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a>) was tested at Ricerca’s (formerly MDS Pharma’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM), and was found to have one hit against Melatonin (MT1) at 75% inhibition.</p></div></div><div id="ml300.s12"><h2 id="_ml300_s12_">4. Discussion</h2><div id="ml300.s13"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Based on recent literature searches, a lack of legitimate non-covalent 3CLpro inhibitors continues to exist. The field has been limited mostly to covalently bound inhibitors.(<a class="bibr" href="#ml300.r1" rid="ml300.r1">1</a>–<a class="bibr" href="#ml300.r5" rid="ml300.r5">5</a> and references therein) Among non-covalent inhibitors to date, these are primarily limited to large refined peptidomimetics with poor inhibitory activity (<a class="bibr" href="#ml300.r4" rid="ml300.r4">4</a>) or so-called small molecules, that in fact maintain a covalent modifier group or reactive elements that would limit their potential for development as an antiviral. A summary of second generation small molecule 3CLpro inhibitors, some containing reactive warhead groups and are known to have a covalent mode of action, are included in <a class="figpopup" href="/books/NBK143547/figure/ml300.f3/?report=objectonly" target="object" rid-figpopup="figml300f3" rid-ob="figobml300f3">Figure 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml300f3" co-legend-rid="figlgndml300f3"><a href="/books/NBK143547/figure/ml300.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml300f3" rid-ob="figobml300f3"><img class="small-thumb" src="/books/NBK143547/bin/ml300f3.gif" src-large="/books/NBK143547/bin/ml300f3.jpg" alt="Figure 3. Second generation small molecule 3CLpro inhibitors." /></a><div class="icnblk_cntnt" id="figlgndml300f3"><h4 id="ml300.f3"><a href="/books/NBK143547/figure/ml300.f3/?report=objectonly" target="object" rid-ob="figobml300f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Second generation small molecule 3CLpro inhibitors. Some contain reactive warhead groups and are known to have a covalent mode of action </p></div></div><p>This probe molecule (<a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a>) is a non-covalent inhibitor of the SARS-CoV 3CLpro enzyme. It is selective against the related PLpro enzyme. This inhibitor can be synthetically accessed in a straight forward four-step sequence and no chiral chromatography is required. Current inhibitors within the covalent modifier class require multiple steps to access a final compound. The 3CLpro-<a href="/pcsubstance/?term=ML188[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML188</a> and SID-<a href="https://pubchem.ncbi.nlm.nih.gov/substance/289" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">289</a> X-ray crystal structures were critical in guiding the optimization process and encouraged the exploration of the P3-truncated effort within the benzotriazole series. With this additional probe 3CLpro inhibitor declared, a renewed interest to develop selective small molecule inhibitors against 3CLpro and other coronavirus proteinase targets will follow as the field continues to search for novel antivirals against SARS and SARS-like infections.</p></div></div><div id="ml300.s14"><h2 id="_ml300_s14_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml300.r1">Anand K, Ziebuhr J, Wadhwani R, Mesters JR, Hilgenfeld R. Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs. <span><span class="ref-journal">Science. </span>2003;<span class="ref-vol">300</span>:1763–1767.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12746549" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12746549</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml300.r2">Ghosh AK, Xi K, Johnson ME, Baker SC, Mesecar AD. Progress in Anti-SARS Coronavirus Chemistry, Biology and Chemotherapy. <span><span class="ref-journal">Ann. Rep. Med. Chem. </span>2006;<span class="ref-vol">41</span>:183–196.</span> [<a href="/pmc/articles/PMC2718771/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2718771</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19649165" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19649165</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml300.r3">Ghosh AK, Gong G, Grum-Tokars V, Mulhearn DC, Baker SC, Coughlin M, Prabhakar BS, Sleeman K, Johnson ME, Mesecar AD. Design, synthesis and antiviral efficacy of a series of potent choropyridyl ester-derived SARS-CoV 3CLpro inhibitors. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2008;<span class="ref-vol">18</span>:5684–5688.</span> [<a href="/pmc/articles/PMC2745596/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2745596</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18796354" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18796354</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml300.r4">Wu C.-Y, Jan J.-T, Ma S.-H, Kuo C.-J, Juan H.-F, Cheng EY.-S, Hsu H.-H, Huang H.-C, Wu D, Brik A, Liang F.-S, Liu R.-S, Fang J.-M, Chen S.-T, Liang P.-H, Wong C.-H. Small molecules targeting severe acute respiratory syndrome human coronavirus. <span><span class="ref-journal">Proc Natl Acad Sci. </span>2004;<span class="ref-vol">101</span>:10012.</span> [<a href="/pmc/articles/PMC454157/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC454157</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15226499" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15226499</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml300.r5">Ghosh AK, Xi K, Ratia K, Santarsiero BD, Fu W, Harcourt BH, Rota PA, Baker SC, Johnson ME, Mesecar AD. Design and Synthesis of Peptidomimetic Severe Acute Respiratory Syndrome Chymotrypsin-like Protease Inhibitors. <span><span class="ref-journal">J Med Chem. </span>2005;<span class="ref-vol">48</span>:6767–6770.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16250632" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16250632</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK143547_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Mark Turlington</span>,<sup>2</sup> <span itemprop="author">Aspen Chun</span>,<sup>2</sup> <span itemprop="author">Jon Jacobs</span>,<sup>2</sup> <span itemprop="author">Eric Dawson</span>,<sup>2</sup> <span itemprop="author">J. Scott Daniels</span>,<sup>2</sup> <span itemprop="author">Adrian Saldanha</span>,<sup>3</sup> <span itemprop="author">Peter Chase</span>,<sup>3</sup> <span itemprop="author">Peter Hodder</span>,<sup>3</sup> <span itemprop="author">Aimee Eggler</span>,<sup>1</sup> <span itemprop="author">Valerie Tokars</span>,<sup>4</sup> <span itemprop="author">Andrew Mesecar</span>,<sup>1</sup> <span itemprop="author">Craig W. Lindsley</span>,<sup>2</sup> and <span itemprop="author">Shaun R. Stauffer</span><sup>2</sup><sup>,*</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Purdue University</div><div class="affiliation"><sup>2</sup>
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Vanderbilt Specialized Chemistry Center for Accelerated Probe Development</div><div class="affiliation"><sup>3</sup>
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Scripps Research Institute Molecular Screening Center</div><div class="affiliation"><sup>4</sup>
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Northwestern University</div><div class="affiliation"><sup>*</sup>
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@reffuats.nuahs" class="oemail">ude.tlibrednav@reffuats.nuahs</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">April 9, 2012</span>; Last Update: <span itemprop="dateModified">March 14, 2013</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Turlington M, Chun A, Jacobs J, et al. Non-covalent triazole-based inhibitors of the SARS main proteinase 3CLpro. 2012 Apr 9 [Updated 2013 Mar 14]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml302/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml299/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml300fu1"><div id="ml300.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK143547/bin/ml300fu1.jpg" alt="Image ml300fu1" /></div></div></article><article data-type="table-wrap" id="figobml300tu1"><div id="ml300.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143547/table/ml300.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml300.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml300.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml300.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml300.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub>(nM) [SID, AID]</th><th id="hd_h_ml300.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml300.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml300.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml300.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]§</th></tr></thead><tbody><tr><td headers="hd_h_ml300.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 46861530/<a href="/pcsubstance/?term=ML300[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML300</a></td><td headers="hd_h_ml300.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3CLpro</td><td headers="hd_h_ml300.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1500 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/99289112" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99289112</a>,<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488967" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488967</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488958" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488958</a>]</td><td headers="hd_h_ml300.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">none</td><td headers="hd_h_ml300.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> = 4.11±0.24</td><td headers="hd_h_ml300.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NA</td><td headers="hd_h_ml300.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NA</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml300tu2"><div id="ml300.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143547/table/ml300.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml300.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AID</th><th id="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Name</th></tr></thead><tbody><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1706" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1706</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QFRET-based primary biochemical high throughput screening assay to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro)</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1859" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1859</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Summary of probe development efforts to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro)</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1879" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1879</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QFRET-based confirmation biochemical high throughput screening assay for inhibitors of the SARS coronavirus 3C-like Protease (3CLPro)</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1890" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1890</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QFRET-based dose response biochemical high throughput screening assay to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro)</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1944" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1944</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Luminescence-based counterscreen for inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): dose response biochemical high throughput screening assay to identify inhibitors of the papain-like protease</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435015" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435015</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage counterscreen results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro); luminescence-based cell-based assay to identify cytotoxic compounds in Vero E6 cells.</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488958" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488958</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical dose-response assay for inhibitors of 3CLPro.</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488877" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488877</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider counterscreen results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): luminescence-based dose-response cell-based assay for restoration of viability of SARS-CoV-infected Vero cells.</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488967" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488967</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical assay for inhibitors of 3CLPro.</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488984" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488984</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical assay for inhibitors of 3CLPro: Set 2</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493245" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493245</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical assay for inhibitors of 3CLPro: Set 3</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488999" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488999</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical dose-response assay for inhibitors of 3CLPro; Set 2</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588772" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588772</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical assay for inhibitors of 3CLPro: Set 4</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588771" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588771</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical dose-response assay for inhibitors of 3CLPro; Set 3.</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588786" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588786</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical dose-response assay for inhibitors of 3CLPro; Set 4.</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602487" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602487</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical assay for inhibitors of 3CLPro: Set 5</td></tr><tr><td headers="hd_h_ml300.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602486" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602486</a></td><td headers="hd_h_ml300.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Late stage assay provider results from the probe development effort to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro): fluorescence-based biochemical dose-response assay for inhibitors of 3CLPro; Set 5</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml300f1"><div id="ml300.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143547/bin/ml300f1.jpg" alt="Figure 1. Synthetic procedure and spectral data for ML300 (CID 46861530)." /></div><h3><span class="label">Figure 1</span><span class="title">Synthetic procedure and spectral data for ML300 (CID 46861530)</span></h3></div></article><article data-type="fig" id="figobml300fu2"><div id="ml300.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK143547/bin/ml300fu2.jpg" alt="Image ml300fu2" /></div></div></article><article data-type="fig" id="figobml300fu3"><div id="ml300.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK143547/bin/ml300fu3.jpg" alt="Image ml300fu3" /></div></div></article><article data-type="fig" id="figobml300fu4"><div id="ml300.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK143547/bin/ml300fu4.jpg" alt="Image ml300fu4" /></div></div></article><article data-type="fig" id="figobml300f2"><div id="ml300.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143547/bin/ml300f2.jpg" alt="Figure 2. M-M Inhibition Curve for ML300." /></div><h3><span class="label">Figure 2</span><span class="title">M-M Inhibition Curve for ML300</span></h3></div></article><article data-type="fig" id="figobml300f3"><div id="ml300.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20Second%20generation%20small%20molecule%203CLpro%20inhibitors.&p=BOOKS&id=143547_ml300f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK143547/bin/ml300f3.jpg" alt="Figure 3. Second generation small molecule 3CLpro inhibitors." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">Second generation small molecule 3CLpro inhibitors</span></h3><div class="caption"><p>Some contain reactive warhead groups and are known to have a covalent mode of action</p></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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