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Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents
Leishmaniasis, a disease caused by protozoa of the species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, th...
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| Published in: | Journal of medicinal chemistry 2021-08, Vol.64 (16), p.12152-12162 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| cites | cdi_FETCH-LOGICAL-c408t-d22ad745b98ce267df73d8379055cb69db9c55b5a49ca262723972eea4e98cfe3 |
| container_end_page | 12162 |
| container_issue | 16 |
| container_start_page | 12152 |
| container_title | Journal of medicinal chemistry |
| container_volume | 64 |
| creator | Hammill, Jared T Sviripa, Vitaliy M Kril, Liliia M Ortiz, Diana Fargo, Corinne M Kim, Ho Shin Chen, Yizhe Rector, Jonah Rice, Amy L Domagalska, Malgorzata A Begley, Kristin L Liu, Chunming Rangnekar, Vivek M Dujardin, Jean-Claude Watt, David S Landfear, Scott M Guy, R Kiplin |
| description | Leishmaniasis, a disease caused by protozoa of the
species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of
parasites with good selectivity relative to the host macrophages. Early lead
was rapidly acting and possessed good potency against
(EC
= 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC
= 3.7 μM), and also blocked proliferation of
parasites resistant to antimonial drugs. Finally, another early lead,
, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs. |
| doi_str_mv | 10.1021/acs.jmedchem.1c00813 |
| format | article |
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species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of
parasites with good selectivity relative to the host macrophages. Early lead
was rapidly acting and possessed good potency against
(EC
= 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC
= 3.7 μM), and also blocked proliferation of
parasites resistant to antimonial drugs. Finally, another early lead,
, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c00813</identifier><identifier>PMID: 34355566</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Female ; Leishmania - drug effects ; Leishmaniasis, Cutaneous - drug therapy ; Mice ; Mice, Inbred BALB C ; Microsomes, Liver - metabolism ; Molecular Structure ; Quinolines - chemical synthesis ; Quinolines - metabolism ; Quinolines - pharmacokinetics ; Quinolines - therapeutic use ; Structure-Activity Relationship ; Trypanocidal Agents - chemical synthesis ; Trypanocidal Agents - metabolism ; Trypanocidal Agents - pharmacokinetics ; Trypanocidal Agents - therapeutic use</subject><ispartof>Journal of medicinal chemistry, 2021-08, Vol.64 (16), p.12152-12162</ispartof><rights>2021 The Authors. Published by American Chemical Society 2021 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-d22ad745b98ce267df73d8379055cb69db9c55b5a49ca262723972eea4e98cfe3</citedby><cites>FETCH-LOGICAL-c408t-d22ad745b98ce267df73d8379055cb69db9c55b5a49ca262723972eea4e98cfe3</cites><orcidid>0000-0002-7272-373X ; 0000-0001-7398-9022 ; 0000-0002-9638-2060 ; 0000-0002-9463-0526</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34355566$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hammill, Jared T</creatorcontrib><creatorcontrib>Sviripa, Vitaliy M</creatorcontrib><creatorcontrib>Kril, Liliia M</creatorcontrib><creatorcontrib>Ortiz, Diana</creatorcontrib><creatorcontrib>Fargo, Corinne M</creatorcontrib><creatorcontrib>Kim, Ho Shin</creatorcontrib><creatorcontrib>Chen, Yizhe</creatorcontrib><creatorcontrib>Rector, Jonah</creatorcontrib><creatorcontrib>Rice, Amy L</creatorcontrib><creatorcontrib>Domagalska, Malgorzata A</creatorcontrib><creatorcontrib>Begley, Kristin L</creatorcontrib><creatorcontrib>Liu, Chunming</creatorcontrib><creatorcontrib>Rangnekar, Vivek M</creatorcontrib><creatorcontrib>Dujardin, Jean-Claude</creatorcontrib><creatorcontrib>Watt, David S</creatorcontrib><creatorcontrib>Landfear, Scott M</creatorcontrib><creatorcontrib>Guy, R Kiplin</creatorcontrib><title>Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Leishmaniasis, a disease caused by protozoa of the
species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of
parasites with good selectivity relative to the host macrophages. Early lead
was rapidly acting and possessed good potency against
(EC
= 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC
= 3.7 μM), and also blocked proliferation of
parasites resistant to antimonial drugs. Finally, another early lead,
, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.</description><subject>Animals</subject><subject>Female</subject><subject>Leishmania - drug effects</subject><subject>Leishmaniasis, Cutaneous - drug therapy</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Microsomes, Liver - metabolism</subject><subject>Molecular Structure</subject><subject>Quinolines - chemical synthesis</subject><subject>Quinolines - metabolism</subject><subject>Quinolines - pharmacokinetics</subject><subject>Quinolines - therapeutic use</subject><subject>Structure-Activity Relationship</subject><subject>Trypanocidal Agents - chemical synthesis</subject><subject>Trypanocidal Agents - metabolism</subject><subject>Trypanocidal Agents - pharmacokinetics</subject><subject>Trypanocidal Agents - therapeutic use</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpVkNtKAzEQhoMotlbfQGRfIHVy2sONsBS1QkFBBe9CNpttU_ZQN1nBtze1B_Rqkpn8_z_5ELomMCVAya3SbrpuTKlXppkSDZASdoLGRFDAPAV-isYAlGIaUzZCF86tAYARys7RiHEmhIjjMfrIG9t2-HUonLd-8KaMGM777xpHqt2e58abvlOh8zmEl7VtjYuUi146b1pvVR3lodTGulWj2t_7MgzcJTqrVO3M1b5O0PvD_dtsjhfPj0-zfIE1h9TjklJVJlwUWaoNjZOySliZsiQDIXQRZ2WRaSEKoXimVfhKQlmWUGMUN0FRGTZBdzvfzVBsaYTsXtVy09smLC07ZeX_SWtXctl9yZQDp0CCAd8Z6L5zrjfVUUtAbknLQFoeSMs96SC7-Zt7FB3Qsh-jwoAX</recordid><startdate>20210826</startdate><enddate>20210826</enddate><creator>Hammill, Jared T</creator><creator>Sviripa, Vitaliy M</creator><creator>Kril, Liliia M</creator><creator>Ortiz, Diana</creator><creator>Fargo, Corinne M</creator><creator>Kim, Ho Shin</creator><creator>Chen, Yizhe</creator><creator>Rector, Jonah</creator><creator>Rice, Amy L</creator><creator>Domagalska, Malgorzata A</creator><creator>Begley, Kristin L</creator><creator>Liu, Chunming</creator><creator>Rangnekar, Vivek M</creator><creator>Dujardin, Jean-Claude</creator><creator>Watt, David S</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>5PM</scope><orcidid>https://orcid.org/0000-0002-7272-373X</orcidid><orcidid>https://orcid.org/0000-0001-7398-9022</orcidid><orcidid>https://orcid.org/0000-0002-9638-2060</orcidid><orcidid>https://orcid.org/0000-0002-9463-0526</orcidid></search><sort><creationdate>20210826</creationdate><title>Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents</title><author>Hammill, Jared T ; Sviripa, Vitaliy M ; Kril, Liliia M ; Ortiz, Diana ; Fargo, Corinne M ; Kim, Ho Shin ; Chen, Yizhe ; Rector, Jonah ; Rice, Amy L ; Domagalska, Malgorzata A ; Begley, Kristin L ; Liu, Chunming ; Rangnekar, Vivek M ; Dujardin, Jean-Claude ; Watt, David S ; Landfear, Scott M ; Guy, R Kiplin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-d22ad745b98ce267df73d8379055cb69db9c55b5a49ca262723972eea4e98cfe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Female</topic><topic>Leishmania - drug effects</topic><topic>Leishmaniasis, Cutaneous - drug therapy</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Microsomes, Liver - metabolism</topic><topic>Molecular Structure</topic><topic>Quinolines - chemical synthesis</topic><topic>Quinolines - metabolism</topic><topic>Quinolines - pharmacokinetics</topic><topic>Quinolines - therapeutic use</topic><topic>Structure-Activity Relationship</topic><topic>Trypanocidal Agents - chemical synthesis</topic><topic>Trypanocidal Agents - metabolism</topic><topic>Trypanocidal Agents - pharmacokinetics</topic><topic>Trypanocidal Agents - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hammill, Jared T</creatorcontrib><creatorcontrib>Sviripa, Vitaliy M</creatorcontrib><creatorcontrib>Kril, Liliia M</creatorcontrib><creatorcontrib>Ortiz, Diana</creatorcontrib><creatorcontrib>Fargo, Corinne M</creatorcontrib><creatorcontrib>Kim, Ho Shin</creatorcontrib><creatorcontrib>Chen, Yizhe</creatorcontrib><creatorcontrib>Rector, Jonah</creatorcontrib><creatorcontrib>Rice, Amy L</creatorcontrib><creatorcontrib>Domagalska, Malgorzata A</creatorcontrib><creatorcontrib>Begley, Kristin L</creatorcontrib><creatorcontrib>Liu, Chunming</creatorcontrib><creatorcontrib>Rangnekar, Vivek M</creatorcontrib><creatorcontrib>Dujardin, Jean-Claude</creatorcontrib><creatorcontrib>Watt, David S</creatorcontrib><creatorcontrib>Landfear, Scott M</creatorcontrib><creatorcontrib>Guy, R Kiplin</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hammill, Jared T</au><au>Sviripa, Vitaliy M</au><au>Kril, Liliia M</au><au>Ortiz, Diana</au><au>Fargo, Corinne M</au><au>Kim, Ho Shin</au><au>Chen, Yizhe</au><au>Rector, Jonah</au><au>Rice, Amy L</au><au>Domagalska, Malgorzata A</au><au>Begley, Kristin L</au><au>Liu, Chunming</au><au>Rangnekar, Vivek M</au><au>Dujardin, Jean-Claude</au><au>Watt, David S</au><au>Landfear, Scott M</au><au>Guy, R Kiplin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2021-08-26</date><risdate>2021</risdate><volume>64</volume><issue>16</issue><spage>12152</spage><epage>12162</epage><pages>12152-12162</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Leishmaniasis, a disease caused by protozoa of the
species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of
parasites with good selectivity relative to the host macrophages. Early lead
was rapidly acting and possessed good potency against
(EC
= 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC
= 3.7 μM), and also blocked proliferation of
parasites resistant to antimonial drugs. Finally, another early lead,
, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34355566</pmid><doi>10.1021/acs.jmedchem.1c00813</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-7272-373X</orcidid><orcidid>https://orcid.org/0000-0001-7398-9022</orcidid><orcidid>https://orcid.org/0000-0002-9638-2060</orcidid><orcidid>https://orcid.org/0000-0002-9463-0526</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2021-08, Vol.64 (16), p.12152-12162 |
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| language | eng |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Female Leishmania - drug effects Leishmaniasis, Cutaneous - drug therapy Mice Mice, Inbred BALB C Microsomes, Liver - metabolism Molecular Structure Quinolines - chemical synthesis Quinolines - metabolism Quinolines - pharmacokinetics Quinolines - therapeutic use Structure-Activity Relationship Trypanocidal Agents - chemical synthesis Trypanocidal Agents - metabolism Trypanocidal Agents - pharmacokinetics Trypanocidal Agents - therapeutic use |
| title | Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents |
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