Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenylpyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound 11b being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.

Pyrrolyl pyrazoles as non-diketo acid inhibitors of the HIV-1 ribonuclease H function of reverse transcriptase / Messore, Antonella; Corona, Angela; Madia, Valentina Noemi; Saccoliti, Francesco; Tudino, Valeria; De Leo, Alessandro; Scipione, Luigi; De Vita, Daniela; Amendola, Giorgio; Di Maro, Salvatore; Novellino, Ettore; Cosconati, Sandro; Métifiot, Mathieu; Andreola, Marie-Line; Valenti, Piera; Esposito, Francesca; Grandi, Nicole; Tramontano, Enzo; Costi, Roberta; Di Santo, Roberto. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 11:5(2020), pp. 798-805. [10.1021/acsmedchemlett.9b00617]

Pyrrolyl pyrazoles as non-diketo acid inhibitors of the HIV-1 ribonuclease H function of reverse transcriptase

Messore, Antonella;Madia, Valentina Noemi;Saccoliti, Francesco;Tudino, Valeria;De Leo, Alessandro;Scipione, Luigi;De Vita, Daniela;Valenti, Piera;Costi, Roberta
;
Di Santo, Roberto
2020

Abstract

Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenylpyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound 11b being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.
2020
AIDS;HIV; RNase H inhibitors; Diketo acid Pyrazole
01 Pubblicazione su rivista::01a Articolo in rivista
Pyrrolyl pyrazoles as non-diketo acid inhibitors of the HIV-1 ribonuclease H function of reverse transcriptase / Messore, Antonella; Corona, Angela; Madia, Valentina Noemi; Saccoliti, Francesco; Tudino, Valeria; De Leo, Alessandro; Scipione, Luigi; De Vita, Daniela; Amendola, Giorgio; Di Maro, Salvatore; Novellino, Ettore; Cosconati, Sandro; Métifiot, Mathieu; Andreola, Marie-Line; Valenti, Piera; Esposito, Francesca; Grandi, Nicole; Tramontano, Enzo; Costi, Roberta; Di Santo, Roberto. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 11:5(2020), pp. 798-805. [10.1021/acsmedchemlett.9b00617]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1408850
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