Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors

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• 作者：Andrea Spallarossa ; Sara Cesarini ; Angelo Ranise ; Olga Bruno ; Silvia Schenone ; Paolo La Colla ; Gabriella Collu ; Giuseppina Sanna ; Barbara Secci ; Roberta Loddo
• 关键词：O-(2-Phthalimidoethyl)-N-arylthiocarbamates ; HIV-1 ; Non-nucleoside reverse transcriptase inhibitors ; Parallel synthesis ; Molecular docking
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 2009
• 年：2009
• 卷：44
• 期：4
• 页码：1650-1663
• 全文大小：580 K

文摘

The structure–activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl) substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC₅₀ = 1.3 μM) with good potency against the K103R mutant (EC₅₀ = 4.8 μM). Docking simulations helped to rationalize the SARs.