Exploring pyrazolines as potential inhibitors of NSP3-macrodomain of SARS-CoV-2: synthesis and in silico analysis
Rekha R. Joshi, Harsh K. Gaikwad, Bhavana Soge, Abdulrahman Alshammari, Norah Abdullah Albekairi, Atul Kabra, Usha Yashwante, Baban S. Kolte, Pradip D. Lokhande, Rohan J. Meshram · Scientific Reports · 2025
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 β-aryl β-anilino ketones react with phenyl hydrazine in potassium hydroxide to give the corresponding 3,5-diarylpyrazoline. The protocol is applicable to a variety of β-amino ketones and tolerates several functional groups. This method is efficient and proceeds regioselectivity since the β-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.