Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides
Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all a...
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| Veröffentlicht in: | Journal of medicinal chemistry 2023-06, Vol.66 (11), p.7374-7386 |
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| container_title | Journal of medicinal chemistry |
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| creator | Kim, Ho Shin Ortiz, Diana Kadayat, Tara Man Fargo, Corinne M. Hammill, Jared T. Chen, Yizhe Rice, Amy L. Begley, Kristin L. Shoeran, Gaurav Pistel, William Yates, Phillip A. Sanchez, Marco A. Landfear, Scott M. Guy, R. Kiplin |
| description | Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure–activity and structure–property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs. |
| doi_str_mv | 10.1021/acs.jmedchem.3c00056 |
| format | Article |
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Kiplin</creator><creatorcontrib>Kim, Ho Shin ; Ortiz, Diana ; Kadayat, Tara Man ; Fargo, Corinne M. ; Hammill, Jared T. ; Chen, Yizhe ; Rice, Amy L. ; Begley, Kristin L. ; Shoeran, Gaurav ; Pistel, William ; Yates, Phillip A. ; Sanchez, Marco A. ; Landfear, Scott M. ; Guy, R. Kiplin</creatorcontrib><description>Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure–activity and structure–property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c00056</identifier><identifier>PMID: 37216489</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antiprotozoal Agents - chemistry ; Benzamides - pharmacology ; Benzamides - therapeutic use ; Humans ; Leishmania ; Leishmaniasis - chemically induced ; Leishmaniasis - drug therapy ; Leishmaniasis - parasitology ; Mice</subject><ispartof>Journal of medicinal chemistry, 2023-06, Vol.66 (11), p.7374-7386</ispartof><rights>2023 The Authors. Published by American Chemical Society</rights><rights>2023 The Authors. Published by American Chemical Society 2023 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a450t-f833db3cb939d88a6b86a71172643906764ca3324339bcc12e048e89b12427683</citedby><cites>FETCH-LOGICAL-a450t-f833db3cb939d88a6b86a71172643906764ca3324339bcc12e048e89b12427683</cites><orcidid>0000-0003-0012-9579 ; 0000-0002-9638-2060</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.3c00056$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00056$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37216489$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Ho Shin</creatorcontrib><creatorcontrib>Ortiz, Diana</creatorcontrib><creatorcontrib>Kadayat, Tara Man</creatorcontrib><creatorcontrib>Fargo, Corinne M.</creatorcontrib><creatorcontrib>Hammill, Jared T.</creatorcontrib><creatorcontrib>Chen, Yizhe</creatorcontrib><creatorcontrib>Rice, Amy L.</creatorcontrib><creatorcontrib>Begley, Kristin L.</creatorcontrib><creatorcontrib>Shoeran, Gaurav</creatorcontrib><creatorcontrib>Pistel, William</creatorcontrib><creatorcontrib>Yates, Phillip A.</creatorcontrib><creatorcontrib>Sanchez, Marco A.</creatorcontrib><creatorcontrib>Landfear, Scott M.</creatorcontrib><creatorcontrib>Guy, R. Kiplin</creatorcontrib><title>Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure–activity and structure–property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.</description><subject>Animals</subject><subject>Antiprotozoal Agents - chemistry</subject><subject>Benzamides - pharmacology</subject><subject>Benzamides - therapeutic use</subject><subject>Humans</subject><subject>Leishmania</subject><subject>Leishmaniasis - chemically induced</subject><subject>Leishmaniasis - drug therapy</subject><subject>Leishmaniasis - parasitology</subject><subject>Mice</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtPwzAQhC0EglL4BwjlyIEUv-I4J0QRLwmpB-BsbRyXGjlxiR0k-PW4tCC4cNrDfjO7mkHoiOAJwZScgQ6Tl9Y0emHaCdMY40JsoREpKM65xHwbjTCmNKeCsj20H8JLQhihbBftsZISwWU1Qg-zZbSt_YBofZf5eTbrwbn3bGo9vIF1UDuTXXTROmPDooXOgsvoKT8t8sfehqEO0cYhmiabmu4DWtuYcIB25uCCOdzMMXq6vnq8vM3vZzd3lxf3OfACx3wuGWtqpuuKVY2UIGopoCSkpIKzCotScA2MUc5YVWtNqMFcGlnVhHJaCsnG6HztuxzqVRCmi-l5textC_278mDV301nF-rZv6mUX1HxgiSHk41D718HE6JqbdDGOeiMH4KikkhccMlEQvka1b0PoTfznzsErwyJSoWo70LUppAkO_7944_ou4EE4DXwJfdD36XI_vf8BOY5mrw</recordid><startdate>20230608</startdate><enddate>20230608</enddate><creator>Kim, Ho Shin</creator><creator>Ortiz, Diana</creator><creator>Kadayat, Tara Man</creator><creator>Fargo, Corinne M.</creator><creator>Hammill, Jared T.</creator><creator>Chen, Yizhe</creator><creator>Rice, Amy L.</creator><creator>Begley, Kristin L.</creator><creator>Shoeran, Gaurav</creator><creator>Pistel, William</creator><creator>Yates, Phillip A.</creator><creator>Sanchez, Marco A.</creator><creator>Landfear, Scott M.</creator><creator>Guy, R. Kiplin</creator><general>American Chemical Society</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0012-9579</orcidid><orcidid>https://orcid.org/0000-0002-9638-2060</orcidid></search><sort><creationdate>20230608</creationdate><title>Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides</title><author>Kim, Ho Shin ; Ortiz, Diana ; Kadayat, Tara Man ; Fargo, Corinne M. ; Hammill, Jared T. ; Chen, Yizhe ; Rice, Amy L. ; Begley, Kristin L. ; Shoeran, Gaurav ; Pistel, William ; Yates, Phillip A. ; Sanchez, Marco A. ; Landfear, Scott M. ; Guy, R. 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Kiplin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2023-06-08</date><risdate>2023</risdate><volume>66</volume><issue>11</issue><spage>7374</spage><epage>7386</epage><pages>7374-7386</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure–activity and structure–property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>37216489</pmid><doi>10.1021/acs.jmedchem.3c00056</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-0012-9579</orcidid><orcidid>https://orcid.org/0000-0002-9638-2060</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2023-06, Vol.66 (11), p.7374-7386 |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Antiprotozoal Agents - chemistry Benzamides - pharmacology Benzamides - therapeutic use Humans Leishmania Leishmaniasis - chemically induced Leishmaniasis - drug therapy Leishmaniasis - parasitology Mice |
| title | Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides |
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