Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum

In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substitu...

Full description

Saved in:
Bibliographic Details
Published in:ACS medicinal chemistry letters 2017-02, Vol.8 (2), p.201-205
Main Authors: Wicht, Kathryn J., Combrinck, Jill M., Smith, Peter J., Hunter, Roger, Egan, Timothy J.
Format: Article
Language:English
Subjects:
Letter
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-a457t-e7c8f171be19f1bb76bb304b119c0d985105a9f235ddb76dc7d997d6b48792503
cites cdi_FETCH-LOGICAL-a457t-e7c8f171be19f1bb76bb304b119c0d985105a9f235ddb76dc7d997d6b48792503
container_end_page 205
container_issue 2
container_start_page 201
container_title ACS medicinal chemistry letters
container_volume 8
creator Wicht, Kathryn J.
Combrinck, Jill M.
Smith, Peter J.
Hunter, Roger
Egan, Timothy J.
description In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of P. falciparum intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.
doi_str_mv 10.1021/acsmedchemlett.6b00416
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5304302</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1868701234</sourcerecordid><originalsourceid>FETCH-LOGICAL-a457t-e7c8f171be19f1bb76bb304b119c0d985105a9f235ddb76dc7d997d6b48792503</originalsourceid><addsrcrecordid>eNqFkctOHDEQRa0oUSDALyAvs2li98vtTSSESBiJCBZkbfnVM4X8mNjuicLXx2gmCFZZ2da9dapcF6FzSi4oaekXqbO3Rm-sd7aUi1ER0tPxHTqmvJ-aYWLD-1f3I_Qp50dCRs4Y-YiO2oly1tH2GP1eGRsKzKBlgRiwDAb_sHojA-QCGl_vpFv2UpzxjfXxKUJoVmEDCgqENX5IINMfBx6MfIrOZnypC-wslmsJIRd872T20cDi8Sydhq1Miz9FH-oj27PDeYJ-frt-uLppbu--r64ubxvZD6w0lulppowqS_lMlWKjUh3pFaVcE8OngZJB8rntBmOqaDQznDMzqn5ivB1Id4K-7rnbRT0vrH42SSe2CXydWkQJ4q0SYCPWcSeG2qYjbQV8PgBS_LXYXISHrK1zMti4ZEGncWKEtl1frePeqlPMOdn5pQ0l4jk18TY1cUitFp6_HvKl7F9M1dDuDRUgHuOSQt3Z_6h_AXxSrao</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1868701234</pqid></control><display><type>article</type><title>Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum</title><source>PubMed Central(OpenAccess)</source><source>American Chemical Society:Jisc Collections:American Chemical Society Read &amp; Publish Agreement 2022-2024 (Reading list)</source><creator>Wicht, Kathryn J. ; Combrinck, Jill M. ; Smith, Peter J. ; Hunter, Roger ; Egan, Timothy J.</creator><creatorcontrib>Wicht, Kathryn J. ; Combrinck, Jill M. ; Smith, Peter J. ; Hunter, Roger ; Egan, Timothy J.</creatorcontrib><description>In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of P. falciparum intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.</description><identifier>ISSN: 1948-5875</identifier><identifier>EISSN: 1948-5875</identifier><identifier>DOI: 10.1021/acsmedchemlett.6b00416</identifier><identifier>PMID: 28197312</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Letter</subject><ispartof>ACS medicinal chemistry letters, 2017-02, Vol.8 (2), p.201-205</ispartof><rights>Copyright © 2017 American Chemical Society</rights><rights>Copyright © 2017 American Chemical Society 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a457t-e7c8f171be19f1bb76bb304b119c0d985105a9f235ddb76dc7d997d6b48792503</citedby><cites>FETCH-LOGICAL-a457t-e7c8f171be19f1bb76bb304b119c0d985105a9f235ddb76dc7d997d6b48792503</cites><orcidid>0000-0001-7720-8473</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304302/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304302/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28197312$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wicht, Kathryn J.</creatorcontrib><creatorcontrib>Combrinck, Jill M.</creatorcontrib><creatorcontrib>Smith, Peter J.</creatorcontrib><creatorcontrib>Hunter, Roger</creatorcontrib><creatorcontrib>Egan, Timothy J.</creatorcontrib><title>Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum</title><title>ACS medicinal chemistry letters</title><addtitle>ACS Med. Chem. Lett</addtitle><description>In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of P. falciparum intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.</description><subject>Letter</subject><issn>1948-5875</issn><issn>1948-5875</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNqFkctOHDEQRa0oUSDALyAvs2li98vtTSSESBiJCBZkbfnVM4X8mNjuicLXx2gmCFZZ2da9dapcF6FzSi4oaekXqbO3Rm-sd7aUi1ER0tPxHTqmvJ-aYWLD-1f3I_Qp50dCRs4Y-YiO2oly1tH2GP1eGRsKzKBlgRiwDAb_sHojA-QCGl_vpFv2UpzxjfXxKUJoVmEDCgqENX5IINMfBx6MfIrOZnypC-wslmsJIRd872T20cDi8Sydhq1Miz9FH-oj27PDeYJ-frt-uLppbu--r64ubxvZD6w0lulppowqS_lMlWKjUh3pFaVcE8OngZJB8rntBmOqaDQznDMzqn5ivB1Id4K-7rnbRT0vrH42SSe2CXydWkQJ4q0SYCPWcSeG2qYjbQV8PgBS_LXYXISHrK1zMti4ZEGncWKEtl1frePeqlPMOdn5pQ0l4jk18TY1cUitFp6_HvKl7F9M1dDuDRUgHuOSQt3Z_6h_AXxSrao</recordid><startdate>20170209</startdate><enddate>20170209</enddate><creator>Wicht, Kathryn J.</creator><creator>Combrinck, Jill M.</creator><creator>Smith, Peter J.</creator><creator>Hunter, Roger</creator><creator>Egan, Timothy J.</creator><general>American Chemical Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7720-8473</orcidid></search><sort><creationdate>20170209</creationdate><title>Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum</title><author>Wicht, Kathryn J. ; Combrinck, Jill M. ; Smith, Peter J. ; Hunter, Roger ; Egan, Timothy J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a457t-e7c8f171be19f1bb76bb304b119c0d985105a9f235ddb76dc7d997d6b48792503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Letter</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wicht, Kathryn J.</creatorcontrib><creatorcontrib>Combrinck, Jill M.</creatorcontrib><creatorcontrib>Smith, Peter J.</creatorcontrib><creatorcontrib>Hunter, Roger</creatorcontrib><creatorcontrib>Egan, Timothy J.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ACS medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wicht, Kathryn J.</au><au>Combrinck, Jill M.</au><au>Smith, Peter J.</au><au>Hunter, Roger</au><au>Egan, Timothy J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum</atitle><jtitle>ACS medicinal chemistry letters</jtitle><addtitle>ACS Med. Chem. Lett</addtitle><date>2017-02-09</date><risdate>2017</risdate><volume>8</volume><issue>2</issue><spage>201</spage><epage>205</epage><pages>201-205</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><abstract>In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of P. falciparum intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28197312</pmid><doi>10.1021/acsmedchemlett.6b00416</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0001-7720-8473</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1948-5875
ispartof ACS medicinal chemistry letters, 2017-02, Vol.8 (2), p.201-205
issn 1948-5875
1948-5875
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5304302
source PubMed Central(OpenAccess); American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
subjects Letter
title Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T06%3A35%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20and%20Mechanistic%20Evaluation%20of%20Hemozoin-Inhibiting%20Triarylimidazoles%20Active%20against%20Plasmodium%20falciparum&rft.jtitle=ACS%20medicinal%20chemistry%20letters&rft.au=Wicht,%20Kathryn%20J.&rft.date=2017-02-09&rft.volume=8&rft.issue=2&rft.spage=201&rft.epage=205&rft.pages=201-205&rft.issn=1948-5875&rft.eissn=1948-5875&rft_id=info:doi/10.1021/acsmedchemlett.6b00416&rft_dat=%3Cproquest_pubme%3E1868701234%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-a457t-e7c8f171be19f1bb76bb304b119c0d985105a9f235ddb76dc7d997d6b48792503%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1868701234&rft_id=info:pmid/28197312&rfr_iscdi=true