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Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies.
- Source :
-
European Journal of Medicinal Chemistry . Oct2013, Vol. 68, p372-384. 13p. - Publication Year :
- 2013
-
Abstract
- Abstract: We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c–k and 5n with the inhibitory activities (K i or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a K i value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (K i = 0.39 μM). In addition, the K i value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 68
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 90634746
- Full Text :
- https://doi.org/10.1016/j.ejmech.2013.07.037