Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors

GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:European journal of medicinal chemistry 2021-12, Vol.225, p.113780-113780, Article 113780
Hauptverfasser: Ma, Yue, Zhao, Shujie, Ren, Yujie, Cherukupalli, Srinivasulu, Li, Qilan, Woodson, Molly E., Bradley, Daniel P., Tavis, John E., Liu, Xinyong, Zhan, Peng
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 113780
container_issue
container_start_page 113780
container_title European journal of medicinal chemistry
container_volume 225
creator Ma, Yue
Zhao, Shujie
Ren, Yujie
Cherukupalli, Srinivasulu
Li, Qilan
Woodson, Molly E.
Bradley, Daniel P.
Tavis, John E.
Liu, Xinyong
Zhan, Peng
description GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitroanti-HBV activity and low cytotoxicity were observed for compound 4r (EC50 = 0.20 ± 0.00 μM, CC50 > 87.03 μM), which was more potent than the positive control lamivudine (EC50 = 0.37 ± 0.04 μM, CC50 > 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC50 = 0.045 ± 0.01 μM, CC50 > 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo. [Display omitted] •Novel heteroaryldihydropyrimidines bearing spiro ring are reported as HBV capsid inhibitors.•Compound 4r exhibited better antiviral activities than lamivudine and low cytotoxicity in vitro.•Compound 4r was predicted to have similar ADMET and PK characteristics as GLS4.
doi_str_mv 10.1016/j.ejmech.2021.113780
format Article
fullrecord <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10591454</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0223523421006292</els_id><sourcerecordid>34438123</sourcerecordid><originalsourceid>FETCH-LOGICAL-c418t-afcbe46a89f1a1039cbb87b813243083cf724505c14e24265d596464f7707e9d3</originalsourceid><addsrcrecordid>eNp9kd2KFDEQhYMo7rj6BiJ5AHvMX__dKLrrHyzszXod0kn1dA09SZNkBuYZfOnN2rrojVdVUOec4vAR8pqzLWe8ebffwv4AdtoKJviWc9l27AnZ8LbpKilq9ZRsmBCyqoVUF-RFSnvGWN0w9pxcSKVkx4XckJ_XkHDn39J09nkqe6LGOwonMx9NxuBpGOkEGWIw8Tw7nM4uhuUc8YAOPRS1mcPuCIkOYCL6HU0LxkB_rSYV71Jycsn9RE8Yj4lasyR0dIkhA3qKfsIBc4jpJXk2mjnBq9_zkvz48vnu6lt1c_v1-9XHm8oq3uXKjHYA1ZiuH7nhTPZ2GLp26LgUSrJO2rEVqma15QqEEk3t6r5RjRrblrXQO3lJPqy5y3E4gLPgczSzXkqn0lEHg_rfi8dJ78JJc1b3XNWqJKg1wcaQUoTx0cyZfqCj93qlox_o6JVOsb35-_Gj6Q-OIni_CqDUPyFEnSyCt-Awgs3aBfz_h3vnJKc7</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors</title><source>MEDLINE</source><source>Access via ScienceDirect (Elsevier)</source><creator>Ma, Yue ; Zhao, Shujie ; Ren, Yujie ; Cherukupalli, Srinivasulu ; Li, Qilan ; Woodson, Molly E. ; Bradley, Daniel P. ; Tavis, John E. ; Liu, Xinyong ; Zhan, Peng</creator><creatorcontrib>Ma, Yue ; Zhao, Shujie ; Ren, Yujie ; Cherukupalli, Srinivasulu ; Li, Qilan ; Woodson, Molly E. ; Bradley, Daniel P. ; Tavis, John E. ; Liu, Xinyong ; Zhan, Peng</creatorcontrib><description>GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitroanti-HBV activity and low cytotoxicity were observed for compound 4r (EC50 = 0.20 ± 0.00 μM, CC50 &gt; 87.03 μM), which was more potent than the positive control lamivudine (EC50 = 0.37 ± 0.04 μM, CC50 &gt; 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC50 = 0.045 ± 0.01 μM, CC50 &gt; 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo. [Display omitted] •Novel heteroaryldihydropyrimidines bearing spiro ring are reported as HBV capsid inhibitors.•Compound 4r exhibited better antiviral activities than lamivudine and low cytotoxicity in vitro.•Compound 4r was predicted to have similar ADMET and PK characteristics as GLS4.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2021.113780</identifier><identifier>PMID: 34438123</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Capsid protein inhibitors ; Capsid Proteins - antagonists &amp; inhibitors ; Capsid Proteins - metabolism ; Dose-Response Relationship, Drug ; Drug Design ; GLS4 ; HBV ; Hepatitis B virus - chemistry ; Hepatitis B virus - drug effects ; Hepatitis B virus - metabolism ; Heteroaryldihydropyrimidine ; Humans ; Microbial Sensitivity Tests ; Molecular Structure ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Scaffold hopping ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2021-12, Vol.225, p.113780-113780, Article 113780</ispartof><rights>2021 Elsevier Masson SAS</rights><rights>Copyright © 2021 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-afcbe46a89f1a1039cbb87b813243083cf724505c14e24265d596464f7707e9d3</citedby><cites>FETCH-LOGICAL-c418t-afcbe46a89f1a1039cbb87b813243083cf724505c14e24265d596464f7707e9d3</cites><orcidid>0000-0002-8711-4240 ; 0000-0001-5836-9853 ; 0000-0002-1156-1036</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2021.113780$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34438123$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Yue</creatorcontrib><creatorcontrib>Zhao, Shujie</creatorcontrib><creatorcontrib>Ren, Yujie</creatorcontrib><creatorcontrib>Cherukupalli, Srinivasulu</creatorcontrib><creatorcontrib>Li, Qilan</creatorcontrib><creatorcontrib>Woodson, Molly E.</creatorcontrib><creatorcontrib>Bradley, Daniel P.</creatorcontrib><creatorcontrib>Tavis, John E.</creatorcontrib><creatorcontrib>Liu, Xinyong</creatorcontrib><creatorcontrib>Zhan, Peng</creatorcontrib><title>Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitroanti-HBV activity and low cytotoxicity were observed for compound 4r (EC50 = 0.20 ± 0.00 μM, CC50 &gt; 87.03 μM), which was more potent than the positive control lamivudine (EC50 = 0.37 ± 0.04 μM, CC50 &gt; 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC50 = 0.045 ± 0.01 μM, CC50 &gt; 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo. [Display omitted] •Novel heteroaryldihydropyrimidines bearing spiro ring are reported as HBV capsid inhibitors.•Compound 4r exhibited better antiviral activities than lamivudine and low cytotoxicity in vitro.•Compound 4r was predicted to have similar ADMET and PK characteristics as GLS4.</description><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Capsid protein inhibitors</subject><subject>Capsid Proteins - antagonists &amp; inhibitors</subject><subject>Capsid Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>GLS4</subject><subject>HBV</subject><subject>Hepatitis B virus - chemistry</subject><subject>Hepatitis B virus - drug effects</subject><subject>Hepatitis B virus - metabolism</subject><subject>Heteroaryldihydropyrimidine</subject><subject>Humans</subject><subject>Microbial Sensitivity Tests</subject><subject>Molecular Structure</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Scaffold hopping</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd2KFDEQhYMo7rj6BiJ5AHvMX__dKLrrHyzszXod0kn1dA09SZNkBuYZfOnN2rrojVdVUOec4vAR8pqzLWe8ebffwv4AdtoKJviWc9l27AnZ8LbpKilq9ZRsmBCyqoVUF-RFSnvGWN0w9pxcSKVkx4XckJ_XkHDn39J09nkqe6LGOwonMx9NxuBpGOkEGWIw8Tw7nM4uhuUc8YAOPRS1mcPuCIkOYCL6HU0LxkB_rSYV71Jycsn9RE8Yj4lasyR0dIkhA3qKfsIBc4jpJXk2mjnBq9_zkvz48vnu6lt1c_v1-9XHm8oq3uXKjHYA1ZiuH7nhTPZ2GLp26LgUSrJO2rEVqma15QqEEk3t6r5RjRrblrXQO3lJPqy5y3E4gLPgczSzXkqn0lEHg_rfi8dJ78JJc1b3XNWqJKg1wcaQUoTx0cyZfqCj93qlox_o6JVOsb35-_Gj6Q-OIni_CqDUPyFEnSyCt-Awgs3aBfz_h3vnJKc7</recordid><startdate>20211205</startdate><enddate>20211205</enddate><creator>Ma, Yue</creator><creator>Zhao, Shujie</creator><creator>Ren, Yujie</creator><creator>Cherukupalli, Srinivasulu</creator><creator>Li, Qilan</creator><creator>Woodson, Molly E.</creator><creator>Bradley, Daniel P.</creator><creator>Tavis, John E.</creator><creator>Liu, Xinyong</creator><creator>Zhan, Peng</creator><general>Elsevier Masson SAS</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>5PM</scope><orcidid>https://orcid.org/0000-0002-8711-4240</orcidid><orcidid>https://orcid.org/0000-0001-5836-9853</orcidid><orcidid>https://orcid.org/0000-0002-1156-1036</orcidid></search><sort><creationdate>20211205</creationdate><title>Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors</title><author>Ma, Yue ; Zhao, Shujie ; Ren, Yujie ; Cherukupalli, Srinivasulu ; Li, Qilan ; Woodson, Molly E. ; Bradley, Daniel P. ; Tavis, John E. ; Liu, Xinyong ; Zhan, Peng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-afcbe46a89f1a1039cbb87b813243083cf724505c14e24265d596464f7707e9d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Capsid protein inhibitors</topic><topic>Capsid Proteins - antagonists &amp; inhibitors</topic><topic>Capsid Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>GLS4</topic><topic>HBV</topic><topic>Hepatitis B virus - chemistry</topic><topic>Hepatitis B virus - drug effects</topic><topic>Hepatitis B virus - metabolism</topic><topic>Heteroaryldihydropyrimidine</topic><topic>Humans</topic><topic>Microbial Sensitivity Tests</topic><topic>Molecular Structure</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Scaffold hopping</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Yue</creatorcontrib><creatorcontrib>Zhao, Shujie</creatorcontrib><creatorcontrib>Ren, Yujie</creatorcontrib><creatorcontrib>Cherukupalli, Srinivasulu</creatorcontrib><creatorcontrib>Li, Qilan</creatorcontrib><creatorcontrib>Woodson, Molly E.</creatorcontrib><creatorcontrib>Bradley, Daniel P.</creatorcontrib><creatorcontrib>Tavis, John E.</creatorcontrib><creatorcontrib>Liu, Xinyong</creatorcontrib><creatorcontrib>Zhan, Peng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Yue</au><au>Zhao, Shujie</au><au>Ren, Yujie</au><au>Cherukupalli, Srinivasulu</au><au>Li, Qilan</au><au>Woodson, Molly E.</au><au>Bradley, Daniel P.</au><au>Tavis, John E.</au><au>Liu, Xinyong</au><au>Zhan, Peng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2021-12-05</date><risdate>2021</risdate><volume>225</volume><spage>113780</spage><epage>113780</epage><pages>113780-113780</pages><artnum>113780</artnum><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitroanti-HBV activity and low cytotoxicity were observed for compound 4r (EC50 = 0.20 ± 0.00 μM, CC50 &gt; 87.03 μM), which was more potent than the positive control lamivudine (EC50 = 0.37 ± 0.04 μM, CC50 &gt; 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC50 = 0.045 ± 0.01 μM, CC50 &gt; 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo. [Display omitted] •Novel heteroaryldihydropyrimidines bearing spiro ring are reported as HBV capsid inhibitors.•Compound 4r exhibited better antiviral activities than lamivudine and low cytotoxicity in vitro.•Compound 4r was predicted to have similar ADMET and PK characteristics as GLS4.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>34438123</pmid><doi>10.1016/j.ejmech.2021.113780</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8711-4240</orcidid><orcidid>https://orcid.org/0000-0001-5836-9853</orcidid><orcidid>https://orcid.org/0000-0002-1156-1036</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 0223-5234
ispartof European journal of medicinal chemistry, 2021-12, Vol.225, p.113780-113780, Article 113780
issn 0223-5234
1768-3254
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10591454
source MEDLINE; Access via ScienceDirect (Elsevier)
subjects Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Capsid protein inhibitors
Capsid Proteins - antagonists & inhibitors
Capsid Proteins - metabolism
Dose-Response Relationship, Drug
Drug Design
GLS4
HBV
Hepatitis B virus - chemistry
Hepatitis B virus - drug effects
Hepatitis B virus - metabolism
Heteroaryldihydropyrimidine
Humans
Microbial Sensitivity Tests
Molecular Structure
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Scaffold hopping
Structure-Activity Relationship
title Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T23%3A08%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Design,%20synthesis%20and%20evaluation%20of%20heteroaryldihydropyrimidine%20analogues%20bearing%20spiro%20ring%20as%20hepatitis%20B%20virus%20capsid%20protein%20inhibitors&rft.jtitle=European%20journal%20of%20medicinal%20chemistry&rft.au=Ma,%20Yue&rft.date=2021-12-05&rft.volume=225&rft.spage=113780&rft.epage=113780&rft.pages=113780-113780&rft.artnum=113780&rft.issn=0223-5234&rft.eissn=1768-3254&rft_id=info:doi/10.1016/j.ejmech.2021.113780&rft_dat=%3Cpubmed_cross%3E34438123%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/34438123&rft_els_id=S0223523421006292&rfr_iscdi=true