Selected article for: "11a benzyl and compound 11a"
Author: Linlin Zhang; Daizong Lin; Yuri Kusov; Yong Nian; Qingjun Ma; Jiang Wang; Albrecht von Brunn; Pieter Leyssen; Kristina Lanko; Johan Neyts; Adriaan de Wilde; Eric J. Snijder; Hong Liu; Rolf Hilgenfeld
Title: Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication
  • Document date: 2020_2_10
    • ID: 7n8p9okf_14
    Snippet: The crystal structures indicated that the fits of the P1' benzyl group of 11a in the S1' pocket and of the P3 cinnamoyl cap in the S3 subsite might be improved (see Fig. 3a -c). Compounds 11b -11e and 11g -11l were synthesized in an attempt to do so; however, none of them showed better inhibitory activity against the majority of the recombinant proteases, compared to the parent compound, 11a (see Supplementary Results). To investigate whether the.....
    Document: The crystal structures indicated that the fits of the P1' benzyl group of 11a in the S1' pocket and of the P3 cinnamoyl cap in the S3 subsite might be improved (see Fig. 3a -c). Compounds 11b -11e and 11g -11l were synthesized in an attempt to do so; however, none of them showed better inhibitory activity against the majority of the recombinant proteases, compared to the parent compound, 11a (see Supplementary Results). To investigate whether the P3 residue of the inhibitor is dispensible, we synthesized compound 11f, which only comprises P2 = Boc, P1 = GlnLactam, and P1' = benzyl. 11f was inactive against all purified proteases and in all replicons tested, but showed some activity against HRV2 in HeLa Rh cells (EC50 = 9.0 µM). A crystal structure of 11f bound to HCoV-NL63 M pro demonstrated that the P2-Boc group entered the S2 pocket (Fig. 3d ). In conclusion, although there is probably room for further improvement, we decided to maintain the original design with P1' = benzyl and P3 = cinnamoyl, and focussed on improving the P2 substituen.

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