Identification of Anthranilic Acid Derivatives as a Novel Class of Allosteric Inhibitors of Hepatitis C NS5B Polymerase.

Abstract

Pages 2108-2116. The PDB codes for the X-ray complexes of compounds 3a and 14i with NS5B were not indicated. Coordinates for the X-ray crystal structures have been deposited into the RCSB Protein Databank at www.rcsb.org/pdb/home/ home.do; the PDB codes for the X-ray complexes of compounds 3a and 14i with NS5B are 2qe5 and 2qe2, respectively.

Combined isotope and enantiomer analysis to assess the fate of phenoxy acids in a heterogeneous geologic setting at an old landfill

“…d 13 C 4-CPP and d 13 C dichlorprop were measured in duplicates and the analytical uncertainty was estimated based on the standard deviation of 4-CPP and dichlorprop standards measured along with the field samples. An enantio-pure form of (S)-4CPP was synthesized from 4-chlorophenol, (R)-methyl-2-hydroxypropanoate (98% optical w a t e r r e s e a r c h 4 7 ( 2 0 1 3 ) 6 3 7 e6 4 9 purity, 96% enantiomeric excess purity and the final product purity 87%) and triphenylphosphine (Nittoli et al, 2007). This authentic standard was taken to verify the identity of peaks in the GCeIRMS chromatogram.…”

Multiple Allosteric Pockets of HCV NS5B Polymerase and its Inhibitors: A Structure Based Insight

“…Compound 68 is fixed into a quasitricyclic conformation by a three-centered intramolecular hydrogen bond between the amide -NH, the carboxylic acid oxygen, and the oxygen of the phenoxy group. Further structural modifications in this series provided compounds 69 and 70, endowed with excellent inhibitory activity (IC 50 = 17 nM) and (IC 50 = 10 nM), respectively [65]. An X-ray crystallographic structural determination of compound 69 with 21 NS5B confirmed that this compound binds at the same site and with similar conformation and hydrogen bonding interactions as compound 68.…”

“…One edge of the hydroxyphenyl ring of the inhibitor rests on the side chains of Met423, Leu419, and Val485 (the floor of the cleft), while the rings faces are surrounded by side chains of Leu497 and Ile482 (the walls of the cleft). The phenolic hydroxyl group enters into a possible 2brl Indole-6-carboxylic acid derivative 1 [22] 2brk Indole-6-carboxylic acid derivative 1 [22] 2dxs Tetracyclic indole derivative 1 [39] 1nhu Phenylalanine analog 2 [20] 1nhv Phenylalanine analog 2 [20] 2qe2 Anthranilic acid derivative 3 [65] 2qe5 Anthranilic acid derivative 3 [65] 1z4u Acrylic acid derivative 3 [67] 1yvf Acrylic acid derivative 3 [66] 2jc0 Pyrrolidine analog 3 [70] 2jc1 Pyrrolidine analog 3 [70] a References [73][74][75] are cited only in this water-mediated (HOH55) hydrogen bond to the backbone of Leu497. The enol oxygen of the central dihydropyran-2-one ring forms a direct hydrogen bond to the backbone of Ser476 and water-mediated (HOH4) hydrogen bond to the backbone of Tyr477.…”

“…Anthranilic acid: As a result of a high throughput screening of a library of compounds from Wyeth Laboratories, for inhibitory activity against NS5B yielded compound 68 (IC 50 = 1.64 μM) (Fig. 24) [65]. Subsequent X-ray crystallographic structural determination of truncated 21 NS5B polymerase in complex with compound 68 revealed that the anthranilate inhibitor was bound to the thumb and palm domains of NS5B, approximately 7.5 Å away from the NTP binding pocket, in a similar manner as that reported for proline sulfonamide and for acrylic acid derivatives (PDB ID: 2QE5) (Fig.…”

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

“…Replacement of the phenoxy group by a phenylamino was also interesting. Optimizations of this phenylamino derivative revealed an advantageous substitution pattern with an ortho methyl acetophenone group (IC 50 = 10 and 17 nM for 32b and 32c , respectively, Table ) . The crystallographic data revealed a different binding mode for anthranilic acids from that of acrylic acid derivatives.…”