The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8
as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50
= 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50
= 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8
efficaciously binds to the intended target hCoV-229E main protease (Mpro
). Moreover, due to the high similarity between hCoV-229E Mpro
and SARS-CoV-2 Mpro
, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro
and promising in terms of energy of binding and docking pose.
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