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.
Highlights
Despite many efforts in declining morbidity and mortality in AIDS patients through the combination antiretroviral therapy, controlling HIV infection remains a global health priority. cART significantly suppresses viral load, preventing the progression to advanced AIDS and improving both the quality and expectancy of patients life1,2
Compound 1 and most of the cHTCs previously reported were characterised by two aromatic rings at both C-2 and C-3 positions of the cHTC scaffold, but they could not be essential for the activity as compared to known inhibitors29
Starting from derivative 1 previously reported by us as an allosteric RNase H inhibitors (RNHIs), new series of compounds based on cHTC and bicyclic/tricyclic oxazinone scaffolds have been developed in this study
Summary
Despite many efforts in declining morbidity and mortality in AIDS patients through the combination antiretroviral therapy (cART), controlling HIV infection remains a global health priority. cART significantly suppresses viral load, preventing the progression to advanced AIDS and improving both the quality and expectancy of patients life. Despite many efforts in declining morbidity and mortality in AIDS patients through the combination antiretroviral therapy (cART), controlling HIV infection remains a global health priority. CART significantly suppresses viral load, preventing the progression to advanced AIDS and improving both the quality and expectancy of patients life. Neither a cure nor eradication of HIV infection is possible yet, due to the development of latent but replication-competent viral forms. The number of newly infected people per year is constant and there is an overall increase of detected drug-resistant variants transmitted among antiretroviral treatment–naïve patients. One approach to minimise the development of drug resistance may rely on compounds endowed with alternative mechanisms of action or new binding sites on traditional targets to complement/enrich the current drugs cocktails
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