Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series
Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-05, Vol.64 (9), p.6085-6136 |
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| creator | Palmer, Michael J Deng, Xiaoyi Watts, Shawn Krilov, Goran Gerasyuto, Aleksey Kokkonda, Sreekanth El Mazouni, Farah White, John White, Karen L Striepen, Josefine Bath, Jade Schindler, Kyra A Yeo, Tomas Shackleford, David M Mok, Sachel Deni, Ioanna Lawong, Aloysus Huang, Ann Chen, Gong Wang, Wen Jayaseelan, Jaya Katneni, Kasiram Patil, Rahul Saunders, Jessica Shahi, Shatrughan P Chittimalla, Rajesh Angulo-Barturen, Iñigo Jiménez-Díaz, María Belén Wittlin, Sergio Tumwebaze, Patrick K Rosenthal, Philip J Cooper, Roland A Aguiar, Anna Caroline Campos Guido, Rafael V. C Pereira, Dhelio B Mittal, Nimisha Winzeler, Elizabeth A Tomchick, Diana R Laleu, Benoît Burrows, Jeremy N Rathod, Pradipsinh K Fidock, David A Charman, Susan A Phillips, Margaret A |
| description | Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes. |
| doi_str_mv | 10.1021/acs.jmedchem.1c00173 |
| format | Article |
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These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c00173</identifier><identifier>PMID: 33876936</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antimalarials - chemistry ; Antimalarials - pharmacology ; Dihydroorotate Dehydrogenase ; Drug Design ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Mice ; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors ; Plasmodium falciparum - drug effects ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2021-05, Vol.64 (9), p.6085-6136</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-eef71957aedcd791cd26b12a83bfd4dc02fade72c54a91e88d88ec415ef496173</citedby><cites>FETCH-LOGICAL-a449t-eef71957aedcd791cd26b12a83bfd4dc02fade72c54a91e88d88ec415ef496173</cites><orcidid>0000-0001-8448-6068 ; 0000-0002-4049-2113 ; 0000-0002-9605-0154 ; 0000-0001-5250-5578</orcidid></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.1c00173$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00173$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,315,781,785,886,2766,27078,27926,27927,56740,56790</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33876936$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Palmer, Michael J</creatorcontrib><creatorcontrib>Deng, Xiaoyi</creatorcontrib><creatorcontrib>Watts, Shawn</creatorcontrib><creatorcontrib>Krilov, Goran</creatorcontrib><creatorcontrib>Gerasyuto, Aleksey</creatorcontrib><creatorcontrib>Kokkonda, Sreekanth</creatorcontrib><creatorcontrib>El Mazouni, Farah</creatorcontrib><creatorcontrib>White, John</creatorcontrib><creatorcontrib>White, Karen L</creatorcontrib><creatorcontrib>Striepen, Josefine</creatorcontrib><creatorcontrib>Bath, Jade</creatorcontrib><creatorcontrib>Schindler, Kyra A</creatorcontrib><creatorcontrib>Yeo, Tomas</creatorcontrib><creatorcontrib>Shackleford, David M</creatorcontrib><creatorcontrib>Mok, Sachel</creatorcontrib><creatorcontrib>Deni, Ioanna</creatorcontrib><creatorcontrib>Lawong, Aloysus</creatorcontrib><creatorcontrib>Huang, Ann</creatorcontrib><creatorcontrib>Chen, Gong</creatorcontrib><creatorcontrib>Wang, Wen</creatorcontrib><creatorcontrib>Jayaseelan, Jaya</creatorcontrib><creatorcontrib>Katneni, Kasiram</creatorcontrib><creatorcontrib>Patil, Rahul</creatorcontrib><creatorcontrib>Saunders, Jessica</creatorcontrib><creatorcontrib>Shahi, Shatrughan P</creatorcontrib><creatorcontrib>Chittimalla, Rajesh</creatorcontrib><creatorcontrib>Angulo-Barturen, Iñigo</creatorcontrib><creatorcontrib>Jiménez-Díaz, María Belén</creatorcontrib><creatorcontrib>Wittlin, Sergio</creatorcontrib><creatorcontrib>Tumwebaze, Patrick K</creatorcontrib><creatorcontrib>Rosenthal, Philip J</creatorcontrib><creatorcontrib>Cooper, Roland A</creatorcontrib><creatorcontrib>Aguiar, Anna Caroline Campos</creatorcontrib><creatorcontrib>Guido, Rafael V. C</creatorcontrib><creatorcontrib>Pereira, Dhelio B</creatorcontrib><creatorcontrib>Mittal, Nimisha</creatorcontrib><creatorcontrib>Winzeler, Elizabeth A</creatorcontrib><creatorcontrib>Tomchick, Diana R</creatorcontrib><creatorcontrib>Laleu, Benoît</creatorcontrib><creatorcontrib>Burrows, Jeremy N</creatorcontrib><creatorcontrib>Rathod, Pradipsinh K</creatorcontrib><creatorcontrib>Fidock, David A</creatorcontrib><creatorcontrib>Charman, Susan A</creatorcontrib><creatorcontrib>Phillips, Margaret A</creatorcontrib><title>Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. 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They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.</description><subject>Animals</subject><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Dihydroorotate Dehydrogenase</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Mice</subject><subject>Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UcFu1DAUtBCILoU_QMhHLllsx0mcC1LZ0rJSpVYqnC3HfmlcJXGwnaLlk_jKOrvbCi6c7OeZN-95BqH3lKwpYfST0mF9P4DRHQxrqgmhVf4CrWjBSMYF4S_RihDGMlay_AS9CeGeEJJTlr9GJ3kuqrLOyxX6c-MijBGfjdEOqlfeqj7gXzZ2-BweoHfTsMAHVsLw1iyX1oLBzQ7fRj_rOHvILmdr0tvGDdMcVbRuTOTrKana3_sSuxYrfLPz3vWQfVEhsc9ttzPeOe9SC6SJ-_IOxoTi7djZxkbn8S14C-EtetWm5eDd8TxFPy6-ft98y66uL7ebs6tMcV7HDKCtaF1UKlljqppqw8qGMiXypjXcaMJaZaBiuuCqpiCEEQI0pwW0vC6Tiafo80F3mpvF3_Rfr3o5-WSQ30mnrPwXGW0n79yDFLSijIsk8PEo4N3PGUKUgw0a-l6N4OYgWUGLUoiCLlR-oGrvQvDQPo-hRC4xyxSzfIpZHmNObR_-XvG56SnXRCAHwr7dzT6lEf6v-QjGg77V</recordid><startdate>20210513</startdate><enddate>20210513</enddate><creator>Palmer, Michael J</creator><creator>Deng, Xiaoyi</creator><creator>Watts, Shawn</creator><creator>Krilov, Goran</creator><creator>Gerasyuto, Aleksey</creator><creator>Kokkonda, Sreekanth</creator><creator>El Mazouni, Farah</creator><creator>White, John</creator><creator>White, Karen L</creator><creator>Striepen, Josefine</creator><creator>Bath, Jade</creator><creator>Schindler, Kyra A</creator><creator>Yeo, Tomas</creator><creator>Shackleford, David M</creator><creator>Mok, Sachel</creator><creator>Deni, Ioanna</creator><creator>Lawong, Aloysus</creator><creator>Huang, Ann</creator><creator>Chen, Gong</creator><creator>Wang, Wen</creator><creator>Jayaseelan, Jaya</creator><creator>Katneni, Kasiram</creator><creator>Patil, Rahul</creator><creator>Saunders, Jessica</creator><creator>Shahi, Shatrughan P</creator><creator>Chittimalla, Rajesh</creator><creator>Angulo-Barturen, Iñigo</creator><creator>Jiménez-Díaz, María Belén</creator><creator>Wittlin, Sergio</creator><creator>Tumwebaze, Patrick K</creator><creator>Rosenthal, Philip J</creator><creator>Cooper, Roland A</creator><creator>Aguiar, Anna Caroline Campos</creator><creator>Guido, Rafael V. 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| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2021-05, Vol.64 (9), p.6085-6136 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8171248 |
| source | MEDLINE; ACS Publications |
| subjects | Animals Antimalarials - chemistry Antimalarials - pharmacology Dihydroorotate Dehydrogenase Drug Design Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Mice Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors Plasmodium falciparum - drug effects Pyrroles - chemistry Pyrroles - pharmacology Structure-Activity Relationship |
| title | Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T05%3A38%3A23IST&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=Potent%20Antimalarials%20with%20Development%20Potential%20Identified%20by%20Structure-Guided%20Computational%20Optimization%20of%20a%20Pyrrole-Based%20Dihydroorotate%20Dehydrogenase%20Inhibitor%20Series&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Palmer,%20Michael%20J&rft.date=2021-05-13&rft.volume=64&rft.issue=9&rft.spage=6085&rft.epage=6136&rft.pages=6085-6136&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.1c00173&rft_dat=%3Cproquest_pubme%3E2515688518%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=2515688518&rft_id=info:pmid/33876936&rfr_iscdi=true |