The main protease (M^pro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered a highly conserved viral target. Disruption of the catalytic activity of M^pro produces a detrimental effect on the course of the infection, making this target one of the most attractive for the treatment of COVID-19. The current success of the SARS-CoV-2 M^pro inhibitor Nirmatrelvir, the first oral drug for the treatment of severe forms of COVID-19, has further focused the attention of researchers on this important viral target, making the search for new M^pro inhibitors a thriving and exciting field for the development of antiviral drugs active against SARS-CoV-2 and related coronaviruses.

The Main Protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered a highly conserved viral target. Disruption of the catalytic activity of Mpro produces a detrimental effect on the course of the infection, making this target one of the most attractive for the treatment of COVID-19. The current success of the SARS-CoV-2 Mpro inhibitor Nirmatrelvir, the first oral drug for the treatment of severe forms of COVID-19, has further focused the attention of researchers on this important viral target, making the search for new Mpro inhibitors a thriving and exciting field for the development of antiviral drugs active against SARS-CoV-2 and related coronaviruses.

Replacing hydrogen with deuterium raises the activation energy for C‒D bond cleavage. This approach has gained attention in drug design, especially to protect the ortho-position of pyridines, which are susceptible to enzymatic oxidation. Until now, direct hydrogen isotope exchange has been largely restricted to the use of reactive organolithium reagents or metal-catalysed deuteration methods. In this work, we present a metal-free, selective ortho-deuteration of N-heterocycles starting from their N-oxides, proceeding at room temperature in just 5 minutes. This method achieves high deuterium incorporation across a broad range of N-heterocycles, including bioactive compounds. Experimental and computational studies have elucidated the mechanism of the reaction, showing that regioselectivity is driven by a successful increase in acidity at the ortho-position, enabling deprotonation by the in-situ generated dimsyl anion.

Pyridines can be deuterated at remote sites by treatment with KOtBu in DMSO-d6, although without discrimination between the meta- and para-position. Herein, base-catalyzed deuterations have been studied, computationally and experimentally, on a series of pyridyl phosphonium and ammonium salts having a temporary electron-withdrawing group to block the para-position while increasing the acidity in the other positions.