From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors

• Main Authors: Serena Massari (Author), Angela Corona (Author), Simona Distinto (Author), Jenny Desantis (Author), Alessia Caredda (Author), Stefano Sabatini (Author), Giuseppe Manfroni (Author), Tommaso Felicetti (Author), Violetta Cecchetti (Author), Christophe Pannecouque (Author), Elias Maccioni (Author), Enzo Tramontano (Author), Oriana Tabarrini (Author)
• Format: Book
• Published: Taylor & Francis Group, 2019-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1475-6366; 1475-6374; 10.1080/14756366.2018.1523901
• Keywords: allosteric inhibitors; antiviral agents; thieno[2,3-d][1,3]oxazin-4-one derivatives; hiv-1 ribonuclease h; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 34, Iss 1, Pp 55-74 (2019)

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.