Exploring novel isatin derivatives as SARS-CoV-2 3CLpro inhibitors.

A series of novel isatin derivatives were synthesised by incorporating phenyl, biphenyl, naphthyl and indolyl moieties into the N-1 position and screened in vitro against SARS-CoV-2 3CLpro, respectively. These isatin compounds with halogen substitution at the isatin ring and trifluoromethylbenzyl substitution at N-1 position were strong inhibitors of SARS-CoV-2 3CLpro. Furthermore, introduction of electron withdrawing groups at the C-5 and C-7 of isatin ring, such as bromo group, might be more favourable for the inhibition activity. The most potent compound 34 demonstrated an IC50 of 0.363 ± 0.045 µM against SARS-CoV-2 3CLpro. Additionally, a jump dilution assay, surface plasmon resonance (SPR) spectroscopy and in silico analysis were used to measure the binding of compound 34 to SARS-CoV-2 3CLpro respectively, supporting the obtained in vitro findings. Moreover, compound 34 inhibited viral cell proliferation with an IC50 of 0.404 ± 0.021 μM (selectivity index (SI) =170). Therefore, it is worth to further investigate compound 34 as a SARS-CoV-2 3CLpro inhibitor.