Efficient Access to 2,3-Diarylimidazo[1,2‑<i>a</i>]pyridines via a One-Pot, Ligand-Free, Palladium-Catalyzed Three-Component Reaction under Microwave Irradiation

An expeditious one-pot, ligand-free, Pd­(OAc)₂-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo­[1,2-<i>a</i>]­pyridines was developed under microwave irradiation. With the high availability of commercial reagents and great efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of 2,3-diarylimidazo­[1,2-<i>a</i>]­pyridines analogues

Discovery of Potent Antivirals against Amantadine-Resistant Influenza A Viruses by Targeting the M2-S31N Proton Channel

Despite the existence of flu vaccines and small-molecule antiviral drugs, influenza virus infection remains a public health concern that warrants immediate attention. As resistance to the only orally bioavailable drug, oseltamivir, has been continuously reported, there is a clear need to develop the next-generation of anti-influenza drugs. We chose the influenza A virus M2-S31N mutant proton channel as the drug target to address this need as it is one of the most conserved viral proteins and persist in >95% of currently circulating influenza A viruses. In this study, we report the development of a late-stage diversification strategy for the expeditious synthesis of M2-S31N inhibitors. The channel blockage and antiviral activity of the synthesized compounds were tested in two-electrode voltage clamp assays and antiviral assays, respectively. Several M2-S31N inhibitors were identified to have potent M2-S31N channel blockage and micromolar antiviral efficacy against several M2-S31N-containing influenza A viruses

Expeditious Lead Optimization of Isoxazole-Containing Influenza A Virus M2-S31N Inhibitors Using the Suzuki–Miyaura Cross-Coupling Reaction

The existence of multidrug-resistant influenza viruses, coupled with the continuously antigenic shift and antigenic drift of influenza viruses, necessitates the development of the next-generation of influenza antivirals. As the AM2-S31N mutant persists in more than 95% of current circulating influenza A viruses, targeting the AM2-S31N proton channel appears to be a logical and valid approach to combating drug resistance. Starting from compound <b>1</b>, an isoxazole compound with potent AM2-S31N channel blockage and antiviral activity, in this study we report an expeditious synthetic strategy that allows us to promptly explore the structure–activity relationships of isoxazole-containing AM2-S31N inhibitors. Propelled by the convenient synthesis, the lead optimization effort yielded a number of potent antivirals with submicromolar efficacy against several human clinical isolates of influenza A viruses, including both oseltamivir-sensitive and -resistant strains

In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses

Influenza viruses are respiratory pathogens that are responsible for both seasonal influenza epidemics and occasional influenza pandemics. The narrow therapeutic window of oseltamivir, coupled with the emergence of drug resistance, calls for the next-generation of antivirals. With our continuous interest in developing AM2-S31N inhibitors as oral influenza antivirals, we report here the progress of optimizing the in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several AM2-S31N inhibitors, including compound <b>10b</b>, were discovered to have potent channel blockage, single to submicromolar antiviral activity, and favorable in vitro PK properties. The antiviral efficacy of compound <b>10b</b> was also synergistic with oseltamivir carboxylate. Interestingly, binding kinetic studies (<i>K</i>_d, <i>K</i>_on, and <i>K</i>_off) revealed several AM2-S31N inhibitors that have similar <i>K</i>_d values but significantly different <i>K</i>_on and <i>K</i>_off values. Overall, this study identified a potent lead compound (<b>10b</b>) with improved in vitro PK properties that is suitable for the in vivo mouse model studies