Studies on Cycloheptathiophene-3-carboxamide Derivatives as Allosteric HIV-1 Ribonuclease H Inhibitors
| Autor: | Oriana Tabarrini, Violetta Cecchetti, Enzo Tramontano, Christophe Pannecouque, Angela Corona, Elias Maccioni, Giuseppe Manfroni, Francesca Esposito, Jenny Desantis, Stefano Sabatini, Serena Massari, Stuart F. J. Le Grice, Simona Distinto, Takashi Masaoka |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Cycloheptathiophene-3-Carboxamides Anti-HIV Agents medicine.drug_class Ribonuclease H Allosteric regulation Carboxamide Context (language use) Thiophenes HIV-1 Ribonuclease H Biology 01 natural sciences Biochemistry Antiviral Agents Article Virus Structure-Activity Relationship 03 medical and health sciences Allosteric Regulation Drug Discovery medicine Structure–activity relationship Enzyme Inhibitors General Pharmacology Toxicology and Pharmaceutics RNase H IC50 Pharmacology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Allosteric Inhibitors Virology Reverse transcriptase 0104 chemical sciences 030104 developmental biology Benzamides HIV-1 biology.protein Molecular Medicine Medicinal Chemistry Allosteric Inhibitors Antiviral Agents Cycloheptathiophene-3-Carboxamides HIV-1 Ribonuclease H Medicinal Chemistry |
| Popis: | Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors. |
| Databáze: | OpenAIRE |
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