From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors. (1st January 2019)

• Record Type: Journal Article
• Authors: Massari, Serena; Corona, Angela; Distinto, Simona; Desantis, Jenny; Caredda, Alessia; Sabatini, Stefano; Manfroni, Giuseppe; Felicetti, Tommaso; Cecchetti, Violetta; Pannecouque, Christophe; Maccioni, Elias; Tramontano, Enzo; Tabarrini, Oriana
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 55
• Page End: 74
• Publication Date: 2019-01-01
• Subjects: Allosteric inhibitors -- antiviral agents -- thieno[2, 3-d][1, 3]oxazin-4-one derivatives -- HIV-1 ribonuclease H; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2018.1523901
• Languages: English
• ISSNs: 1475-6366

Abstract

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 IC50 s 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: