Design, Synthesis, and Preclinical Evaluations of Novel 4‑Substituted 1,5-Diarylanilines as Potent HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates
Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-08, Vol.55 (16), p.7219-7229 |
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| container_title | Journal of medicinal chemistry |
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| creator | Sun, Lian-Qi Zhu, Lei Qian, Keduo Qin, Bingjie Huang, Li Chen, Chin Ho Lee, Kuo-Hsiung Xie, Lan |
| description | Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29–0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1–90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values ( |
| doi_str_mv | 10.1021/jm3007678 |
| format | Article |
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As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29–0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1–90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å2). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm3007678</identifier><identifier>PMID: 22856541</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Aniline Compounds - chemical synthesis ; Aniline Compounds - chemistry ; Aniline Compounds - pharmacology ; Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - pharmacology ; Cell Line ; Drug Design ; Drug Resistance, Viral ; HIV Reverse Transcriptase - metabolism ; HIV-1 - drug effects ; HIV-1 - genetics ; Humans ; In Vitro Techniques ; Microsomes, Liver - metabolism ; Mutation ; Reverse Transcriptase Inhibitors - chemical synthesis ; Reverse Transcriptase Inhibitors - chemistry ; Reverse Transcriptase Inhibitors - pharmacology ; Solubility ; Stereoisomerism ; Structure-Activity Relationship ; Virus Replication</subject><ispartof>Journal of medicinal chemistry, 2012-08, Vol.55 (16), p.7219-7229</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a405t-531a9f201674b1226c42b042a0a210ba7af330db06c818422e333cec3a1d1b13</citedby><cites>FETCH-LOGICAL-a405t-531a9f201674b1226c42b042a0a210ba7af330db06c818422e333cec3a1d1b13</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/jm3007678$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm3007678$$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/22856541$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Lian-Qi</creatorcontrib><creatorcontrib>Zhu, Lei</creatorcontrib><creatorcontrib>Qian, Keduo</creatorcontrib><creatorcontrib>Qin, Bingjie</creatorcontrib><creatorcontrib>Huang, Li</creatorcontrib><creatorcontrib>Chen, Chin Ho</creatorcontrib><creatorcontrib>Lee, Kuo-Hsiung</creatorcontrib><creatorcontrib>Xie, Lan</creatorcontrib><title>Design, Synthesis, and Preclinical Evaluations of Novel 4‑Substituted 1,5-Diarylanilines as Potent HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29–0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1–90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å2). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.</description><subject>Aniline Compounds - chemical synthesis</subject><subject>Aniline Compounds - chemistry</subject><subject>Aniline Compounds - pharmacology</subject><subject>Anti-HIV Agents - chemical synthesis</subject><subject>Anti-HIV Agents - chemistry</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Cell Line</subject><subject>Drug Design</subject><subject>Drug Resistance, Viral</subject><subject>HIV Reverse Transcriptase - metabolism</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - genetics</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Microsomes, Liver - metabolism</subject><subject>Mutation</subject><subject>Reverse Transcriptase Inhibitors - chemical synthesis</subject><subject>Reverse Transcriptase Inhibitors - chemistry</subject><subject>Reverse Transcriptase Inhibitors - pharmacology</subject><subject>Solubility</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Virus Replication</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkdGKEzEUhoMobl298AUkN4ILHT05yUy7N4K0q1tY6rJbvB3OZDJtyjQpSaawd76Cz-Ib-SRGqkXBq5xwvv9Pfn7GXgp4KwDFu-1OAkyqyfQRG4kSoVBTUI_ZCACxwArlGXsW4xYApED5lJ0hTsuqVGLEvs9NtGs35vcPLm3yHMecXMtvg9G9dVZTz68O1A-UrHeR-44v_cH0XP34-u1-aGKyaUim5WJcFnNL4aEnZ7PSRE6R3_pkXOLXiy8ZF1nqiuWge-OjbQ2_MwcTouGrQC7qYPeJ8m3hNraxyQf-Zrm8Wy0u-DwMaz7L37ItJROfsycd9dG8-H2es9XHq9Xsurj5_Gkx-3BTkIIyFaUUdNkhiGqiGoFYaYUNKCQgFNDQhDopoW2g0lMxVYhGSqmNliRa0Qh5zt4fbfdDszOtzkEC9fU-2F2OWXuy9b8bZzf12h9qqSosLzEbXBwNdPAxBtOdtALqX8XVp-Iy--rvx07kn6Yy8PoIkI711g_B5ej_MfoJV7ajJw</recordid><startdate>20120823</startdate><enddate>20120823</enddate><creator>Sun, Lian-Qi</creator><creator>Zhu, Lei</creator><creator>Qian, Keduo</creator><creator>Qin, Bingjie</creator><creator>Huang, Li</creator><creator>Chen, Chin Ho</creator><creator>Lee, Kuo-Hsiung</creator><creator>Xie, Lan</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></search><sort><creationdate>20120823</creationdate><title>Design, Synthesis, and Preclinical Evaluations of Novel 4‑Substituted 1,5-Diarylanilines as Potent HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates</title><author>Sun, Lian-Qi ; Zhu, Lei ; Qian, Keduo ; Qin, Bingjie ; Huang, Li ; Chen, Chin Ho ; Lee, Kuo-Hsiung ; Xie, Lan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a405t-531a9f201674b1226c42b042a0a210ba7af330db06c818422e333cec3a1d1b13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Aniline Compounds - chemical synthesis</topic><topic>Aniline Compounds - chemistry</topic><topic>Aniline Compounds - pharmacology</topic><topic>Anti-HIV Agents - chemical synthesis</topic><topic>Anti-HIV Agents - chemistry</topic><topic>Anti-HIV Agents - pharmacology</topic><topic>Cell Line</topic><topic>Drug Design</topic><topic>Drug Resistance, Viral</topic><topic>HIV Reverse Transcriptase - metabolism</topic><topic>HIV-1 - drug effects</topic><topic>HIV-1 - genetics</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Microsomes, Liver - metabolism</topic><topic>Mutation</topic><topic>Reverse Transcriptase Inhibitors - chemical synthesis</topic><topic>Reverse Transcriptase Inhibitors - chemistry</topic><topic>Reverse Transcriptase Inhibitors - pharmacology</topic><topic>Solubility</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Virus Replication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Lian-Qi</creatorcontrib><creatorcontrib>Zhu, Lei</creatorcontrib><creatorcontrib>Qian, Keduo</creatorcontrib><creatorcontrib>Qin, Bingjie</creatorcontrib><creatorcontrib>Huang, Li</creatorcontrib><creatorcontrib>Chen, Chin Ho</creatorcontrib><creatorcontrib>Lee, Kuo-Hsiung</creatorcontrib><creatorcontrib>Xie, Lan</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>Sun, Lian-Qi</au><au>Zhu, Lei</au><au>Qian, Keduo</au><au>Qin, Bingjie</au><au>Huang, Li</au><au>Chen, Chin Ho</au><au>Lee, Kuo-Hsiung</au><au>Xie, Lan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Preclinical Evaluations of Novel 4‑Substituted 1,5-Diarylanilines as Potent HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-08-23</date><risdate>2012</risdate><volume>55</volume><issue>16</issue><spage>7219</spage><epage>7229</epage><pages>7219-7229</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29–0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1–90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å2). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22856541</pmid><doi>10.1021/jm3007678</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2012-08, Vol.55 (16), p.7219-7229 |
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| subjects | Aniline Compounds - chemical synthesis Aniline Compounds - chemistry Aniline Compounds - pharmacology Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Cell Line Drug Design Drug Resistance, Viral HIV Reverse Transcriptase - metabolism HIV-1 - drug effects HIV-1 - genetics Humans In Vitro Techniques Microsomes, Liver - metabolism Mutation Reverse Transcriptase Inhibitors - chemical synthesis Reverse Transcriptase Inhibitors - chemistry Reverse Transcriptase Inhibitors - pharmacology Solubility Stereoisomerism Structure-Activity Relationship Virus Replication |
| title | Design, Synthesis, and Preclinical Evaluations of Novel 4‑Substituted 1,5-Diarylanilines as Potent HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates |
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