1. From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
- Author
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Alessia Caredda, Violetta Cecchetti, Enzo Tramontano, Serena Massari, Jenny Desantis, Simona Distinto, Elias Maccioni, Tommaso Felicetti, Angela Corona, Stefano Sabatini, Giuseppe Manfroni, Christophe Pannecouque, and Oriana Tabarrini
- Subjects
Anti-HIV Agents ,medicine.drug_class ,Stereochemistry ,Allosteric regulation ,thieno[2,3-d][1,3]oxazin-4-one derivatives ,Carboxamide ,Oxazines ,Thiophenes ,01 natural sciences ,Molecular Docking Simulation ,Cell Line ,Structure-Activity Relationship ,3-d][1 ,Drug Discovery ,antiviral agents ,medicine ,Humans ,Structure–activity relationship ,RNase H ,thieno[2 ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,lcsh:RM1-950 ,HIV ,3]oxazin-4-one derivatives ,General Medicine ,Reverse transcriptase ,0104 chemical sciences ,HIV-1 ribonuclease H ,010404 medicinal & biomolecular chemistry ,lcsh:Therapeutics. Pharmacology ,Ribonuclease H, Human Immunodeficiency Virus ,chemistry ,Cell culture ,biology.protein ,Reverse Transcriptase Inhibitors ,Allosteric inhibitors ,Research Paper ,Allosteric inhibitors, antiviral agents, thieno[2,3-d][1,3]oxazin-4-one derivatives, HIV-1 ribonuclease H - Abstract
The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify oxazinone-based compounds as new anti-RNase H chemotypes. The presence of the catechol moiety at the C-2 position of the scaffold emerged as critical to achieve potent anti-RNase H activity, which also encompassed anti-RNA dependent DNA polymerase (RDDP) activity for the tricyclic derivatives. Benzothienooxazinone derivative 22 resulted the most potent dual inhibitor exhibiting IC50s of 0.53 and 2.90 μM against the RNase H and RDDP functions. Mutagenesis and docking studies suggested that compound 22 binds two allosteric pockets within the RT, one located between the RNase H active site and the primer grip region and the other close to the DNA polymerase catalytic centre., Graphical Abstract
- Published
- 2019