Synthesis and evaluation of C-5 modified 2′-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase
[Display omitted] A series of 5′-monophosphates of 5-substituted 2′-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2015-11, Vol.23 (22), p.7131-7137 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Alexandrova, Liudmila A. Chekhov, Vladimir O. Shmalenyuk, Eduard R. Kochetkov, Sergey N. El-Asrar, Rania Abu Herdewijn, Piet |
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A series of 5′-monophosphates of 5-substituted 2′-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2′-deoxyuridine 5′-monophosphate 3b, displaying an IC50 value against ThyX of 8.32μM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX. |
| doi_str_mv | 10.1016/j.bmc.2015.09.053 |
| format | Article |
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A series of 5′-monophosphates of 5-substituted 2′-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2′-deoxyuridine 5′-monophosphate 3b, displaying an IC50 value against ThyX of 8.32μM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2015.09.053</identifier><identifier>PMID: 26482569</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>2′-Deoxyuridine analogs ; Antitubercular Agents - chemical synthesis ; Antitubercular Agents - chemistry ; Antitubercular Agents - pharmacology ; Bacterial Proteins - antagonists & inhibitors ; Bacterial Proteins - metabolism ; Binding Sites ; Deoxyuridine - analogs & derivatives ; Deoxyuridine - chemical synthesis ; Deoxyuridine - pharmacology ; Enzyme Activation - drug effects ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Inhibition ; Molecular Docking Simulation ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - enzymology ; Nucleoside 5′-monophosphates ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Thymidylate synthase ; Thymidylate Synthase - antagonists & inhibitors ; Thymidylate Synthase - metabolism</subject><ispartof>Bioorganic & medicinal chemistry, 2015-11, Vol.23 (22), p.7131-7137</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-2aa6c93abb72e50125b168f7f47acff4793e054ebd62c3bc2dcafcce22e2cb143</citedby><cites>FETCH-LOGICAL-c396t-2aa6c93abb72e50125b168f7f47acff4793e054ebd62c3bc2dcafcce22e2cb143</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2015.09.053$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3554,27933,27934,46004</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26482569$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alexandrova, Liudmila A.</creatorcontrib><creatorcontrib>Chekhov, Vladimir O.</creatorcontrib><creatorcontrib>Shmalenyuk, Eduard R.</creatorcontrib><creatorcontrib>Kochetkov, Sergey N.</creatorcontrib><creatorcontrib>El-Asrar, Rania Abu</creatorcontrib><creatorcontrib>Herdewijn, Piet</creatorcontrib><title>Synthesis and evaluation of C-5 modified 2′-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
A series of 5′-monophosphates of 5-substituted 2′-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2′-deoxyuridine 5′-monophosphate 3b, displaying an IC50 value against ThyX of 8.32μM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX.</description><subject>2′-Deoxyuridine analogs</subject><subject>Antitubercular Agents - chemical synthesis</subject><subject>Antitubercular Agents - chemistry</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacterial Proteins - antagonists & inhibitors</subject><subject>Bacterial Proteins - metabolism</subject><subject>Binding Sites</subject><subject>Deoxyuridine - analogs & derivatives</subject><subject>Deoxyuridine - chemical synthesis</subject><subject>Deoxyuridine - pharmacology</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Inhibition</subject><subject>Molecular Docking Simulation</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Mycobacterium tuberculosis - enzymology</subject><subject>Nucleoside 5′-monophosphates</subject><subject>Protein Structure, Tertiary</subject><subject>Structure-Activity Relationship</subject><subject>Thymidylate synthase</subject><subject>Thymidylate Synthase - antagonists & inhibitors</subject><subject>Thymidylate Synthase - metabolism</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kLuO1DAUhi0EYoeFB6BBLmkSfIsTiwqNlou0iAKoLV9OFI-SeLCTFangmXgkngRHs1DSHBfn-_8jfwg9p6SmhMpXp9pOrmaENjVRNWn4A3SgQoqKc0UfogNRsqtIp-QVepLziRDChKKP0RWTomONVAf04_M2LwPkkLGZPYY7M65mCXHGscfHqsFT9KEP4DH7_fNX5SF-39YUfJihrOZ4HmI-D2aBks84zEOwYYkp7_GPNV5WC8mtY9wPLMM2Bb-NhcZ5P2syPEWPejNmeHb_XqOvb2--HN9Xt5_efTi-ua0cV3KpmDHSKW6sbRk0hLLGUtn1bS9a4_oyFQfSCLBeMsetY96Z3jlgDJizVPBr9PLSe07x2wp50VPIDsbRzBDXrGnLadsJwVhB6QV1KeacoNfnFCaTNk2J3r3rky7e9e5dE6WL95J5cV-_2gn8v8Rf0QV4fQGgfPIuQNLZBZgd-JDALdrH8J_6P7ZUl7A</recordid><startdate>20151115</startdate><enddate>20151115</enddate><creator>Alexandrova, Liudmila A.</creator><creator>Chekhov, Vladimir O.</creator><creator>Shmalenyuk, Eduard R.</creator><creator>Kochetkov, Sergey N.</creator><creator>El-Asrar, Rania Abu</creator><creator>Herdewijn, Piet</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20151115</creationdate><title>Synthesis and evaluation of C-5 modified 2′-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase</title><author>Alexandrova, Liudmila A. ; Chekhov, Vladimir O. ; Shmalenyuk, Eduard R. ; Kochetkov, Sergey N. ; El-Asrar, Rania Abu ; Herdewijn, Piet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-2aa6c93abb72e50125b168f7f47acff4793e054ebd62c3bc2dcafcce22e2cb143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>2′-Deoxyuridine analogs</topic><topic>Antitubercular Agents - chemical synthesis</topic><topic>Antitubercular Agents - chemistry</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Bacterial Proteins - antagonists & inhibitors</topic><topic>Bacterial Proteins - metabolism</topic><topic>Binding Sites</topic><topic>Deoxyuridine - analogs & derivatives</topic><topic>Deoxyuridine - chemical synthesis</topic><topic>Deoxyuridine - pharmacology</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Inhibition</topic><topic>Molecular Docking Simulation</topic><topic>Mycobacterium tuberculosis</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Mycobacterium tuberculosis - enzymology</topic><topic>Nucleoside 5′-monophosphates</topic><topic>Protein Structure, Tertiary</topic><topic>Structure-Activity Relationship</topic><topic>Thymidylate synthase</topic><topic>Thymidylate Synthase - antagonists & inhibitors</topic><topic>Thymidylate Synthase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alexandrova, Liudmila A.</creatorcontrib><creatorcontrib>Chekhov, Vladimir O.</creatorcontrib><creatorcontrib>Shmalenyuk, Eduard R.</creatorcontrib><creatorcontrib>Kochetkov, Sergey N.</creatorcontrib><creatorcontrib>El-Asrar, Rania Abu</creatorcontrib><creatorcontrib>Herdewijn, Piet</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alexandrova, Liudmila A.</au><au>Chekhov, Vladimir O.</au><au>Shmalenyuk, Eduard R.</au><au>Kochetkov, Sergey N.</au><au>El-Asrar, Rania Abu</au><au>Herdewijn, Piet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of C-5 modified 2′-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2015-11-15</date><risdate>2015</risdate><volume>23</volume><issue>22</issue><spage>7131</spage><epage>7137</epage><pages>7131-7137</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
A series of 5′-monophosphates of 5-substituted 2′-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2′-deoxyuridine 5′-monophosphate 3b, displaying an IC50 value against ThyX of 8.32μM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26482569</pmid><doi>10.1016/j.bmc.2015.09.053</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 2′-Deoxyuridine analogs Antitubercular Agents - chemical synthesis Antitubercular Agents - chemistry Antitubercular Agents - pharmacology Bacterial Proteins - antagonists & inhibitors Bacterial Proteins - metabolism Binding Sites Deoxyuridine - analogs & derivatives Deoxyuridine - chemical synthesis Deoxyuridine - pharmacology Enzyme Activation - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Inhibition Molecular Docking Simulation Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - enzymology Nucleoside 5′-monophosphates Protein Structure, Tertiary Structure-Activity Relationship Thymidylate synthase Thymidylate Synthase - antagonists & inhibitors Thymidylate Synthase - metabolism |
| title | Synthesis and evaluation of C-5 modified 2′-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase |
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