Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety

Abstract

We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.

Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure–activity relationship study

“…The g-lactam-thiazoles (24) were synthesized using an approach similar to the syntheses reported previously [21,22,31]. Accordingly, the optically pure L-glutamic acid ester 21 was converted to the g-lactam ester 22 by treatment with bromoacetonitrile, followed by reduction with PtO 2 (5%) and cyclization.…”

“…1) as a SARS inhibitor revealed that the introduction of an aryloxyacetyl at the N-terminal position (the P4 position) appeared to significantly enhance the inhibitory activity against SARS-CoV 3CL pro [22]. 1) as a SARS inhibitor revealed that the introduction of an aryloxyacetyl at the N-terminal position (the P4 position) appeared to significantly enhance the inhibitory activity against SARS-CoV 3CL pro [22].…”

“…The binding mode of compound 26m with 3CL pro was simulated using a molecular docking program as described previously [22]. We examined the molecular docking of the potent active compound 26m in comparison with docking of the tripeptidic 9 and a structurally similar ligand, the docking structure of which has been elucidated previously by X-ray crystallography (PDB ID: 1WOF, [35].…”

“…Compound 22 was prepared through sequential reactions from the well-known intermediate 21, as reported previously [20e 22,31].…”

“…Very recently, the first case of a fatal respiratory illness similar to the deadly SARS was confirmed in Britain [14]. Two of these compounds (8 and 9), recently described in a separate report from our group [22], exhibited excellent potent inhibitory activities with K i values of 4.1 and 3.1 nM, respectively. There is a significant need to develop anti-SARS agents that are capable of treating this potentially fatal respiratory illness.…”