Exploring pyrazolines as potential inhibitors of NSP3-macrodomain of SARS-CoV-2: synthesis and in silico analysis

COVID-19 has proved to be a global health crisis during the pandemic, and the emerging JN.1 variant is a potential threat. Therefore, finding alternative antivirals is of utmost priority. In the current report, we present the synthesis of new and potential anti-viral pyrazoline compounds. Here we report a chemical scheme where beta-aryl beta-anilino ketones react with phenyl hydrazine in potassium hydroxide to give the corresponding 3,5-diarylpyrazoline. The protocol is applicable to a variety of beta-amino ketones and tolerates several functional groups. This method is efficient and proceeds regioselectivity since the beta-Anilino group acts as a protecting group for alkenes of chalcones. We identified the NSP3-microdomain (Mac-1) of SARS-CoV-2 as a putative target for newly synthesized triaryl-2-pyrazoline compounds. The molecular dynamics simulation-based free energy estimation suggests compounds 7a, 7d, 7 g, 7i, 7k, and 7 L as promising Mac-1 inhibitors. The detailed structural inspection of MD simulation trajectories sheds light on the structural and functional dynamics involved in the SARS-CoV-2 Mac-1. The data presented here is expected to guide the design and development of better anti-SARS-CoV-2 therapies.