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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.

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 (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki 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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Thanigaimalai P,Konno S,Yamamoto T,Koiwai Y,Taguchi A,Takayama K,Yakushiji F,Akaji K,Chen SE,Naser-Tavakolian A,Schön A,Freire E,Hayashi Y

doi

10.1016/j.ejmech.2013.07.037

subject

Has Abstract

pub_date

2013-10-01 00:00:00

pages

372-84

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(13)00485-6

journal_volume

68

pub_type

杂志文章

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