title: 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.
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Konno
authors.forename: Pillaiyar
authors.initials: P
authors.lastname: Thanigaimalai
authors.forename: Takehito
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Nakada
authors.forename: Rie
authors.initials: R
authors.lastname: Kakiuchi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takayama
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Fumika
authors.initials: F
authors.lastname: Yakushiji
authors.forename: Kenichi
authors.initials: K
authors.lastname: Akaji
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Shen-En
authors.initials: SE
authors.lastname: Chen
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000378:metabolism; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D009842:Oligopeptides; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; C005465:benzothiazole