Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB
[Display omitted] Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stere...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2020-09, Vol.30 (18), p.127439-127439, Article 127439 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Matos, Thiago Kelvin Brito Batista, Pedro Henrique Jatai dos Reis Rocho, Fernanda de Vita, Daniela Pearce, Nicholas Kellam, Barrie Montanari, Carlos Alberto Leitão, Andrei |
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Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.82), which was also selective for human cathepsin B (pKi |
| doi_str_mv | 10.1016/j.bmcl.2020.127439 |
| format | Article |
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Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.82), which was also selective for human cathepsin B (pKi < 5). The inversion of the stereochemistry from S to R was more detrimental to potency when placed at the P2 position than at P3. The p-Br derivatives were more potent than the p-CH3 and p-OCH3 derivatives, probably due to intermolecular interactions with the S3 subsite.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2020.127439</identifier><identifier>PMID: 32717373</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Additive effect ; Crystallographic structure ; Dipeptidyl nitrile derivatives ; Enzymatic inhibitors ; SAR</subject><ispartof>Bioorganic & medicinal chemistry letters, 2020-09, Vol.30 (18), p.127439-127439, Article 127439</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-a56efead8fcc1ca4d355e0714804593e37ca92f830913efa8536ee50efca123d3</citedby><cites>FETCH-LOGICAL-c356t-a56efead8fcc1ca4d355e0714804593e37ca92f830913efa8536ee50efca123d3</cites><orcidid>0000-0002-5463-9577 ; 0000-0003-0030-9908 ; 0000-0002-2088-5059</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X20305503$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32717373$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matos, Thiago Kelvin Brito</creatorcontrib><creatorcontrib>Batista, Pedro Henrique Jatai</creatorcontrib><creatorcontrib>dos Reis Rocho, Fernanda</creatorcontrib><creatorcontrib>de Vita, Daniela</creatorcontrib><creatorcontrib>Pearce, Nicholas</creatorcontrib><creatorcontrib>Kellam, Barrie</creatorcontrib><creatorcontrib>Montanari, Carlos Alberto</creatorcontrib><creatorcontrib>Leitão, Andrei</creatorcontrib><title>Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.82), which was also selective for human cathepsin B (pKi < 5). The inversion of the stereochemistry from S to R was more detrimental to potency when placed at the P2 position than at P3. The p-Br derivatives were more potent than the p-CH3 and p-OCH3 derivatives, probably due to intermolecular interactions with the S3 subsite.</description><subject>Additive effect</subject><subject>Crystallographic structure</subject><subject>Dipeptidyl nitrile derivatives</subject><subject>Enzymatic inhibitors</subject><subject>SAR</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kE1LAzEQhoMotlb_gAfJ0cvWfO4HeNHiFxQUVPAW0uwsTcnu1iRb6L83terR08DMM-8wD0LnlEwpofnVarpojZsywlKDFYJXB2hMRS4yLog8RGNS5SQrK_ExQichrAihgghxjEacFbTgBR8j97rt4hKCDVh3NW51NEtItXdgBqc9Xmvr00i77Y7pG2z6jXbQRexhAz7YhQNsu6Vd2Nj7byLlYbMNEWwHeO37CDoAnr3cnqKjRrsAZz91gt7v795mj9n8-eFpdjPPDJd5zLTMoQFdl40x1GhRcymBFFSURMiKAy-MrlhTclJRDo0uJc8BJIHGaMp4zSfocp-bjn8OEKJqbTDgnO6gH4JigpUkZ0LyhLI9anwfgodGrb1ttd8qStTOslqpnWW1s6z2ltPSxU_-sGih_lv51ZqA6z0A6cuNBa-CsdAZqK0HE1Xd2__yvwBoIY_R</recordid><startdate>20200915</startdate><enddate>20200915</enddate><creator>Matos, Thiago Kelvin Brito</creator><creator>Batista, Pedro Henrique Jatai</creator><creator>dos Reis Rocho, Fernanda</creator><creator>de Vita, Daniela</creator><creator>Pearce, Nicholas</creator><creator>Kellam, Barrie</creator><creator>Montanari, Carlos Alberto</creator><creator>Leitão, Andrei</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-5463-9577</orcidid><orcidid>https://orcid.org/0000-0003-0030-9908</orcidid><orcidid>https://orcid.org/0000-0002-2088-5059</orcidid></search><sort><creationdate>20200915</creationdate><title>Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB</title><author>Matos, Thiago Kelvin Brito ; Batista, Pedro Henrique Jatai ; dos Reis Rocho, Fernanda ; de Vita, Daniela ; Pearce, Nicholas ; Kellam, Barrie ; Montanari, Carlos Alberto ; Leitão, Andrei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-a56efead8fcc1ca4d355e0714804593e37ca92f830913efa8536ee50efca123d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Additive effect</topic><topic>Crystallographic structure</topic><topic>Dipeptidyl nitrile derivatives</topic><topic>Enzymatic inhibitors</topic><topic>SAR</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matos, Thiago Kelvin Brito</creatorcontrib><creatorcontrib>Batista, Pedro Henrique Jatai</creatorcontrib><creatorcontrib>dos Reis Rocho, Fernanda</creatorcontrib><creatorcontrib>de Vita, Daniela</creatorcontrib><creatorcontrib>Pearce, Nicholas</creatorcontrib><creatorcontrib>Kellam, Barrie</creatorcontrib><creatorcontrib>Montanari, Carlos Alberto</creatorcontrib><creatorcontrib>Leitão, Andrei</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matos, Thiago Kelvin Brito</au><au>Batista, Pedro Henrique Jatai</au><au>dos Reis Rocho, Fernanda</au><au>de Vita, Daniela</au><au>Pearce, Nicholas</au><au>Kellam, Barrie</au><au>Montanari, Carlos Alberto</au><au>Leitão, Andrei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2020-09-15</date><risdate>2020</risdate><volume>30</volume><issue>18</issue><spage>127439</spage><epage>127439</epage><pages>127439-127439</pages><artnum>127439</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.82), which was also selective for human cathepsin B (pKi < 5). The inversion of the stereochemistry from S to R was more detrimental to potency when placed at the P2 position than at P3. The p-Br derivatives were more potent than the p-CH3 and p-OCH3 derivatives, probably due to intermolecular interactions with the S3 subsite.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>32717373</pmid><doi>10.1016/j.bmcl.2020.127439</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-5463-9577</orcidid><orcidid>https://orcid.org/0000-0003-0030-9908</orcidid><orcidid>https://orcid.org/0000-0002-2088-5059</orcidid></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2020-09, Vol.30 (18), p.127439-127439, Article 127439 |
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| source | Elsevier ScienceDirect Journals |
| subjects | Additive effect Crystallographic structure Dipeptidyl nitrile derivatives Enzymatic inhibitors SAR |
| title | Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB |
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