Design, Synthesis, and Antiviral Activity of Fragmented-Lapatinib Aminoquinazoline Analogs towards SARS-CoV-2 Inhibition

The severe impact of COVID-19 on global health and economies highlights the critical need for innovative treatments. Recently, lapatinib, a drug initially used for breast cancer, has been identified as a potential inhibitor of the main protease (Mpro) of SARS-CoV-2, meriting further investigation. Utilizing rational design strategies and guided by MD simulations, we developed novel aminoquinazoline analogs based on fragmented lapatinib's structure. Preliminary computational screenings identified promising candidates, which were synthesized using a concise 3-4 step process. In vitro assays demonstrated notable antiviral efficacy against SARS-CoV-2-infected cells for all analogs, with Bb1 showing an EC₅₀ of 1.10 μM and significantly lower toxicity (13.55% at 50 μM) compared to lapatinib. Further studies confirmed that these analogs effectively inhibit SARS-CoV-2 Mpro, with Bb7 displaying the highest activity. MD simulations revealed that Bb7 achieves stability within the Mpro binding pocket through interactions with specific residues. These findings indicate that aminoquinazoline analogs hold significant promise as therapeutic candidates for COVID-19.