Dataset Information

Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.

ABSTRACT: The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.

SUBMITTER: Zheng B

PROVIDER: S-EPMC5807875 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.

Zheng Barbara B D'Andrea Stanley V SV Sun Li-Qiang LQ Wang Alan Xiangdong AX Chen Yan Y Hrnciar Peter P Friborg Jacques J Falk Paul P Hernandez Dennis D Yu Fei F Sheaffer Amy K AK Knipe Jay O JO Mosure Kathy K Rajamani Ramkumar R Good Andrew C AC Kish Kevin K Tredup Jeffrey J Klei Herbert E HE Paruchuri Manjula M Ng Alicia A Gao Qi Q Rampulla Richard A RA Mathur Arvind A Meanwell Nicholas A NA McPhee Fiona F Scola Paul M PM

ACS medicinal chemistry letters 20180119 2

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF<sub>2</sub> moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold comp ...[more]

PMID: 29456803

Dataset Information

Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.

Publications

Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.

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