Multifunctional Pyrazolo[3,4-d]Pyrimidine Analogs (HCQ-PPs): Design, Synthesis and Anti-SARS-CoV-2 Evaluation

The novel, highly infectious SARS-CoV-2 virus caused millions of deaths and infections globally. At the same time, the emerged drug repurposing strategy may ultimately not yield a significant clinical benefit. Herein, we designed and synthesized a novel class of pyrazolo[3,4-d]pyrimidines (HCQ-PPs) whose structures were verified by spectral and analytical means as novel anti-SARS-CoV-2 agents. CPE-inhibition assay emerged the 6-((2-hydroxyethyl)aminomethyl) HCQ-PP-1 as the most active analog, exposing about 50% and 29% inhibition compared to remdesivir (88.75% and 70.42% inhibition) at 100 and 10 µM, respectively, indicating the pivotal role of N1, C3 and C4 functionalization. The docking results displayed a unique binding mode of HCQ-PP-1 in the SARS-CoV-2 M^pro binding pocket that could underlie its potential activity with FRED energies of −7.71 comparable to that of remdesivir (-6.71). Its drug-likeness properties met the criteria of Pfizer with an excellent ADMET profile. Therefore, this study presents a novel anti-SARS-CoV-2 lead compound that is worthy of further investigation and activity improvement.