Synthesis and biological evaluation of new conformationally restricted S-DABO hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase
A series of conformationally restricted dihydro-alkylthio-benzyl- oxopyrimidine (S-DABO) hybrids, which combined the structural features of C6-α-methylbenzyl-thio-DABOs (α-methyl-S-DABOs) and C6-α-cyanobenzyl-thio-DABOs (CN-S-DABOs), has been synthesized and biologically evaluated for their anti-HIV...
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| Veröffentlicht in: | Medicinal Chemistry Communications 2014-05, Vol.5 (4), p.468-473 |
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| container_title | Medicinal Chemistry Communications |
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| creator | Wu, Hai-Qiu Pannecouque, Christophe Yan, Zi-Hong Chen, Wen-Xue He, Qiu-Qiu Chen, Fen-Er Balzarini, Jan Daelemans, Dirk De Clercq, Erik |
| description | A series of conformationally restricted dihydro-alkylthio-benzyl- oxopyrimidine (S-DABO) hybrids, which combined the structural features of C6-α-methylbenzyl-thio-DABOs (α-methyl-S-DABOs) and C6-α-cyanobenzyl-thio-DABOs (CN-S-DABOs), has been synthesized and biologically evaluated for their anti-HIV activity against wild-type HIV-1 strain IIIB, double RT mutant (K103N + Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Most of these compounds exhibited inhibitory activity (wild-type) within the range of EC50 values from micromolar to nanomolar. Among them, compound 1s displayed the highest anti-HIV-1 activity with an EC50 value of 91 nM and a selectivity index (SI) of 548, which was more potent than zalcitabine and comparable to nevirapine and delavirdine in the same assay. The HIV-1 reverse transcriptase inhibitory (RT) assay confirmed that these conformationally restricted S-DABO hybrids targeted HIV-1 RT. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of conformationally constrained CN-S-DABO hybrids were also investigated. © 2014 the Partner Organisations. |
| format | Article |
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Most of these compounds exhibited inhibitory activity (wild-type) within the range of EC50 values from micromolar to nanomolar. Among them, compound 1s displayed the highest anti-HIV-1 activity with an EC50 value of 91 nM and a selectivity index (SI) of 548, which was more potent than zalcitabine and comparable to nevirapine and delavirdine in the same assay. The HIV-1 reverse transcriptase inhibitory (RT) assay confirmed that these conformationally restricted S-DABO hybrids targeted HIV-1 RT. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of conformationally constrained CN-S-DABO hybrids were also investigated. © 2014 the Partner Organisations.</description><identifier>ISSN: 2040-2503</identifier><language>eng</language><publisher>CAMBRIDGE: Royal Society of Chemistry</publisher><ispartof>Medicinal Chemistry Communications, 2014-05, Vol.5 (4), p.468-473</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,315,780,784,27860</link.rule.ids></links><search><creatorcontrib>Wu, Hai-Qiu</creatorcontrib><creatorcontrib>Pannecouque, Christophe</creatorcontrib><creatorcontrib>Yan, Zi-Hong</creatorcontrib><creatorcontrib>Chen, Wen-Xue</creatorcontrib><creatorcontrib>He, Qiu-Qiu</creatorcontrib><creatorcontrib>Chen, Fen-Er</creatorcontrib><creatorcontrib>Balzarini, Jan</creatorcontrib><creatorcontrib>Daelemans, Dirk</creatorcontrib><creatorcontrib>De Clercq, Erik</creatorcontrib><title>Synthesis and biological evaluation of new conformationally restricted S-DABO hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase</title><title>Medicinal Chemistry Communications</title><description>A series of conformationally restricted dihydro-alkylthio-benzyl- oxopyrimidine (S-DABO) hybrids, which combined the structural features of C6-α-methylbenzyl-thio-DABOs (α-methyl-S-DABOs) and C6-α-cyanobenzyl-thio-DABOs (CN-S-DABOs), has been synthesized and biologically evaluated for their anti-HIV activity against wild-type HIV-1 strain IIIB, double RT mutant (K103N + Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Most of these compounds exhibited inhibitory activity (wild-type) within the range of EC50 values from micromolar to nanomolar. Among them, compound 1s displayed the highest anti-HIV-1 activity with an EC50 value of 91 nM and a selectivity index (SI) of 548, which was more potent than zalcitabine and comparable to nevirapine and delavirdine in the same assay. The HIV-1 reverse transcriptase inhibitory (RT) assay confirmed that these conformationally restricted S-DABO hybrids targeted HIV-1 RT. 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Most of these compounds exhibited inhibitory activity (wild-type) within the range of EC50 values from micromolar to nanomolar. Among them, compound 1s displayed the highest anti-HIV-1 activity with an EC50 value of 91 nM and a selectivity index (SI) of 548, which was more potent than zalcitabine and comparable to nevirapine and delavirdine in the same assay. The HIV-1 reverse transcriptase inhibitory (RT) assay confirmed that these conformationally restricted S-DABO hybrids targeted HIV-1 RT. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of conformationally constrained CN-S-DABO hybrids were also investigated. © 2014 the Partner Organisations.</abstract><cop>CAMBRIDGE</cop><pub>Royal Society of Chemistry</pub><oa>free_for_read</oa></addata></record> |
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| source | Lirias (KU Leuven Association); Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection |
| title | Synthesis and biological evaluation of new conformationally restricted S-DABO hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase |
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