Pseudo-Dipeptide Bearing α,α<italic/>-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses
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) <...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/3/1398 |
| Summary: | 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) <b>8</b> 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 (EC<sub>50</sub> = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC<sub>50</sub> = 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 <b>8</b> efficaciously binds to the intended target hCoV-229E main protease (M<sup>pro</sup>). Moreover, due to the high similarity between hCoV-229E M<sup>pro</sup> and SARS-CoV-2 M<sup>pro</sup>, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E M<sup>pro</sup> and promising in terms of energy of binding and docking pose. |
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| ISSN: | 1661-6596 1422-0067 |