Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity
Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to ide...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-06, Vol.59 (11), p.5416-5431 |
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| creator | Kokkonda, Sreekanth Deng, Xiaoyi White, Karen L Coteron, Jose M Marco, Maria de las Heras, Laura White, John El Mazouni, Farah Tomchick, Diana R Manjalanagara, Krishne Rudra, Kakali Rani Chen, Gong Morizzi, Julia Ryan, Eileen Kaminsky, Werner Leroy, Didier Martínez-Martínez, María Santos Jimenez-Diaz, Maria Belen Bazaga, Santiago Ferrer Angulo-Barturen, Iñigo Waterson, David Burrows, Jeremy N Matthews, Dave Charman, Susan A Phillips, Margaret A Rathod, Pradipsinh K |
| description | Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen. |
| doi_str_mv | 10.1021/acs.jmedchem.6b00275 |
| format | Article |
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The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b00275</identifier><identifier>PMID: 27127993</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>60 APPLIED LIFE SCIENCES ; anatomy ; Animals ; Antimalarials - chemical synthesis ; Antimalarials - chemistry ; Antimalarials - pharmacology ; assays ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; inhibition ; Malaria, Falciparum - drug therapy ; Mice ; Mice, SCID ; Molecular Structure ; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors ; Oxidoreductases Acting on CH-CH Group Donors - metabolism ; parasites ; Parasitic Sensitivity Tests ; Plasmodium falciparum ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - enzymology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Rats ; rodent models ; Structure-Activity Relationship ; Triazoles - chemical synthesis ; Triazoles - chemistry ; Triazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2016-06, Vol.59 (11), p.5416-5431</ispartof><rights>Copyright © 2016 American Chemical Society</rights><rights>Copyright © 2016 American Chemical Society 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a575t-53b47aa9da01b0707ef6a2adc8ae84a5dba656bc53e436392ba14552da4a8b123</citedby><cites>FETCH-LOGICAL-a575t-53b47aa9da01b0707ef6a2adc8ae84a5dba656bc53e436392ba14552da4a8b123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b00275$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b00275$$EHTML$$P50$$Gacs$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27127993$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1267477$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Kokkonda, Sreekanth</creatorcontrib><creatorcontrib>Deng, Xiaoyi</creatorcontrib><creatorcontrib>White, Karen L</creatorcontrib><creatorcontrib>Coteron, Jose M</creatorcontrib><creatorcontrib>Marco, Maria</creatorcontrib><creatorcontrib>de las Heras, Laura</creatorcontrib><creatorcontrib>White, John</creatorcontrib><creatorcontrib>El Mazouni, Farah</creatorcontrib><creatorcontrib>Tomchick, Diana R</creatorcontrib><creatorcontrib>Manjalanagara, Krishne</creatorcontrib><creatorcontrib>Rudra, Kakali Rani</creatorcontrib><creatorcontrib>Chen, Gong</creatorcontrib><creatorcontrib>Morizzi, Julia</creatorcontrib><creatorcontrib>Ryan, Eileen</creatorcontrib><creatorcontrib>Kaminsky, Werner</creatorcontrib><creatorcontrib>Leroy, Didier</creatorcontrib><creatorcontrib>Martínez-Martínez, María Santos</creatorcontrib><creatorcontrib>Jimenez-Diaz, Maria Belen</creatorcontrib><creatorcontrib>Bazaga, Santiago Ferrer</creatorcontrib><creatorcontrib>Angulo-Barturen, Iñigo</creatorcontrib><creatorcontrib>Waterson, David</creatorcontrib><creatorcontrib>Burrows, Jeremy N</creatorcontrib><creatorcontrib>Matthews, Dave</creatorcontrib><creatorcontrib>Charman, Susan A</creatorcontrib><creatorcontrib>Phillips, Margaret A</creatorcontrib><creatorcontrib>Rathod, Pradipsinh K</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States)</creatorcontrib><title>Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. 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antagonists & inhibitors</subject><subject>Oxidoreductases Acting on CH-CH Group Donors - metabolism</subject><subject>parasites</subject><subject>Parasitic Sensitivity Tests</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats</subject><subject>rodent models</subject><subject>Structure-Activity Relationship</subject><subject>Triazoles - chemical synthesis</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>EIF</sourceid><recordid>eNqFUs1u1DAQjhCILoU3QCji1EsW27Hj5IK0agtUqkQllrM1cbwbV44dbKdSOPEKfQxeiyfB-9MKLnCyZ_zN982Mvyx7jdESI4LfgQzL20F1slfDsmoRIpw9yRaYEVTQGtGn2SLlSEEqUp5kL0K4RQiVmJTPsxPCMeFNUy6yn2sVPfRz511BCgtjH_vZ5GC7nPz6cX9lO7ApXnsN351x4-z1oDttVcjX4LcqarvNbwyEwXV6GvINGKlH8Ol6ofe0zrsIUeUXah9ulYWQIh1GA3N-46Kyca_3RRklo75T-cpGPYCBJGry1S6n4_wye5bIg3p1PE-zrx8u1-efiuvPH6_OV9cFMM5iwcqWcoCmA4RbxBFXmwoIdLIGVVNgXQsVq1rJSkXLqmxIC5gyRjqgULdpPafZ-wPvOLW79ab2PBgxpsHBz8KBFn-_WN2LrbsTtEGU0CoRvD0QuBC1CFJHJXvprE3TCUwqTjlPoLOjinffJhWiGHSQyhiwyk1B4BrVVUkoIv-H8obVVd2gJkHpASq9C8GrzWPbGImda0RyjXhwjTi6JpW9-XPkx6IHmyQAOgD25W7yNv3Avzl_Aw-X2G8</recordid><startdate>20160609</startdate><enddate>20160609</enddate><creator>Kokkonda, Sreekanth</creator><creator>Deng, Xiaoyi</creator><creator>White, Karen L</creator><creator>Coteron, Jose M</creator><creator>Marco, Maria</creator><creator>de las Heras, Laura</creator><creator>White, John</creator><creator>El Mazouni, Farah</creator><creator>Tomchick, Diana R</creator><creator>Manjalanagara, Krishne</creator><creator>Rudra, Kakali Rani</creator><creator>Chen, Gong</creator><creator>Morizzi, Julia</creator><creator>Ryan, Eileen</creator><creator>Kaminsky, Werner</creator><creator>Leroy, Didier</creator><creator>Martínez-Martínez, María Santos</creator><creator>Jimenez-Diaz, Maria Belen</creator><creator>Bazaga, Santiago Ferrer</creator><creator>Angulo-Barturen, Iñigo</creator><creator>Waterson, David</creator><creator>Burrows, Jeremy N</creator><creator>Matthews, Dave</creator><creator>Charman, Susan A</creator><creator>Phillips, Margaret A</creator><creator>Rathod, Pradipsinh K</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</general><scope>N~.</scope><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><scope>C1K</scope><scope>F1W</scope><scope>H95</scope><scope>H97</scope><scope>L.G</scope><scope>M7N</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20160609</creationdate><title>Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity</title><author>Kokkonda, Sreekanth ; Deng, Xiaoyi ; White, Karen L ; Coteron, Jose M ; Marco, Maria ; de las Heras, Laura ; White, John ; El Mazouni, Farah ; Tomchick, Diana R ; Manjalanagara, Krishne ; Rudra, Kakali Rani ; Chen, Gong ; Morizzi, Julia ; Ryan, Eileen ; Kaminsky, Werner ; Leroy, Didier ; Martínez-Martínez, María Santos ; Jimenez-Diaz, Maria Belen ; Bazaga, Santiago Ferrer ; Angulo-Barturen, Iñigo ; Waterson, David ; Burrows, Jeremy N ; Matthews, Dave ; Charman, Susan A ; Phillips, Margaret A ; Rathod, Pradipsinh K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a575t-53b47aa9da01b0707ef6a2adc8ae84a5dba656bc53e436392ba14552da4a8b123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>anatomy</topic><topic>Animals</topic><topic>Antimalarials - 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Med. Chem</addtitle><date>2016-06-09</date><risdate>2016</risdate><volume>59</volume><issue>11</issue><spage>5416</spage><epage>5431</epage><pages>5416-5431</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27127993</pmid><doi>10.1021/acs.jmedchem.6b00275</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2016-06, Vol.59 (11), p.5416-5431 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4904246 |
| source | MEDLINE; ACS Publications |
| subjects | 60 APPLIED LIFE SCIENCES anatomy Animals Antimalarials - chemical synthesis Antimalarials - chemistry Antimalarials - pharmacology assays Disease Models, Animal Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans inhibition Malaria, Falciparum - drug therapy Mice Mice, SCID Molecular Structure Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors Oxidoreductases Acting on CH-CH Group Donors - metabolism parasites Parasitic Sensitivity Tests Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - enzymology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Rats rodent models Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology |
| title | Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T20%3A48%3A53IST&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=Tetrahydro-2-naphthyl%20and%202%E2%80%91Indanyl%20Triazolopyrimidines%20Targeting%20Plasmodium%20falciparum%20Dihydroorotate%20Dehydrogenase%20Display%20Potent%20and%20Selective%20Antimalarial%20Activity&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Kokkonda,%20Sreekanth&rft.aucorp=Argonne%20National%20Laboratory%20(ANL),%20Argonne,%20IL%20(United%20States)&rft.date=2016-06-09&rft.volume=59&rft.issue=11&rft.spage=5416&rft.epage=5431&rft.pages=5416-5431&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.6b00275&rft_dat=%3Cproquest_pubme%3E1808632402%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1795868909&rft_id=info:pmid/27127993&rfr_iscdi=true |