ml9b00617_si_001.pdf (969.65 kB)
Pyrrolyl Pyrazoles as Non-Diketo Acid Inhibitors of the HIV‑1 Ribonuclease H Function of Reverse Transcriptase
journal contribution
posted on 2020-03-13, 18:45 authored by Antonella Messore, Angela Corona, Valentina Noemi Madia, Francesco Saccoliti, Valeria Tudino, Alessandro De Leo, Luigi Scipione, Daniela De Vita, Giorgio Amendola, Salvatore Di Maro, Ettore Novellino, Sandro Cosconati, Mathieu Métifiot, Marie-Line Andreola, Piera Valenti, Francesca Esposito, Nicole Grandi, Enzo Tramontano, Roberta Costi, Roberto Di SantoDue 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.