%0 Journal Article
%T From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
%A Alessia Caredda
%A Angela Corona
%A Christophe Pannecouque
%A Elias Maccioni
%A Enzo Tramontano
%A Giuseppe Manfroni
%A Jenny Desantis
%A Oriana Tabarrini
%A Serena Massari
%A Simona Distinto
%A Stefano Sabatini
%A Tommaso Felicetti
%A Violetta Cecchetti
%J Journal of Enzyme Inhibition and Medicinal Chemistry
%D 2019
%R https://doi.org/10.1080/14756366.2018.1523901
%X 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£¿¦ÌM 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 Abstrac
%U https://www.tandfonline.com/doi/full/10.1080/14756366.2018.1523901