Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors

College of Sciences, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: .
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 11/2013; 22(1). DOI: 10.1016/j.bmc.2013.11.028
Source: PubMed


The Severe Acute Respiratory Syndrome (SARS) is a serious life-threatening and strikingly mortal respiratory illness caused by SARS-CoV. SARS-CoV which contains a chymotrypsin-like main protease analogous to that of the main picornavirus protease, 3CL(pro). 3CL(pro) plays a pivotal role in the viral replication cycle and is a potential target for SARS inhibitor development. A series of isatin derivatives as possible SARS-CoV 3CL(pro) inhibitors was designed, synthesized, and evaluated by in vitro protease assay using fluorogenic substrate peptide, in which several showed potent inhibition against the 3CL(pro). Structure-activity relationship was analyzed, and possible binding interaction modes were proposed by molecular docking studies. Among all compounds, 8k1 showed most potent inhibitory activity against 3CL(pro) (IC50=1.04μM). These results indicated that these inhibitors could be potentially developed into anti-SARS drugs.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ACE inhibitory activity of pistachio (Pistacia vera L.) kernel's hydrolysates by gastrointestinal enzymes was studied. Results indicated that hydrolysate successively hydrolyzed by pepsin and trypsin, Pe-Tr-H, presented in vitro ACE inhibitory activity as IC50 0.87 ± 0.04 mg/ml. The Pe-Tr-H can in vivo decrease around 22 mmHg in systolic blood pressure (SBP) and 16 mmHg in the diastolic blood pressure (DBP) at 4 h after the oral administration, however the pistachio kernel powder can slightly lower SBP and DBP. The Pe-Tr-H with the highest activity was then separated by ultrafiltration membrane of 3 kDa, size exclusion chromatography on Sephadex G-15 and G-10 columns and reversed phase high-performance liquid chromatography (RP-HPLC) consecutively. A novel ACE inhibitory peptide, ACKEP, with the IC50 value of 126 μM, was identified by MALDI-TOF/TOF system. ACKEP has the same C-terminal residue as Lisinopril and Enalapril, which plays a key role in binding with ACE. The binding mechanism was explored at a molecular basis by docking experiments, which revealed that seven residues from ACE active site (His383, His387, Glu384, Arg522, Asp358, Ala356 and Asn70) and two atoms of ACKEP (O5, H60) greatly contributed to the combinative stabilization.
    Full-text · Article · May 2014 · PROCESS BIOCHEMISTRY
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aryl- and N-substituted isatins were converted to isa-tin-3-hydrazones and subjected to a dichlorination re-action with PhICl2. Lewis base-catalysis was key to the reaction occurring rapidly and chemoselectively, providing 3,3-dichloroindolin-2-ones in 49-99% yield, and offering a new approach to the deoxygenative di-halogenation reaction.
    Full-text · Article · Nov 2014 · Organic & Biomolecular Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α−nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CLpro, which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CLpro inhibitor. X-ray crystallographic analyses of the SARS 3CLpro in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.
    No preview · Article · Dec 2014 · Bioorganic & Medicinal Chemistry
Show more