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 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF 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 CH and CF analogues, respectively, providing insight into the deployment of this unique amino acid.

Difluorodiazoethane (CF2HCHN2): A New Reagent for the Introduction of the Difluoromethyl Group

“…[19] Other bioactive molecule containing the difluoromethyl group are highlighted in Figure 3. [20,21] In summary,t he uniquep hysicochemical properties of a CHF 2 group-high metabolic stability compared with the methyl group, lower lipophilicity compared with the CF 3 group, and hydrogen-bond ability-make it an important substituent for drug discovery and agrochemistry.…”

Recent Progress on the Synthesis of CF2H-Containing Derivatives

“…17 Indeed, several examples displaying the involvement of H-bond interactions by this group at the active sites of receptors were reported. [18][19][20][21] Recently, this issue was investigated by us 22,23 by determining the solute H-bond acidity (A, the ability of a molecule to act as a H-bond donor) of various difluoromethylated compounds. The results revealed that the CF 2 H group acts as a relatively weak H-bond donor, with A values that strongly depend on the attached functional group (i.e., FGCF 2 H, A = 0.035-0.165) (Figure 1, A).…”

Aromatic fluorocopolymers based on α-(difluoromethyl)styrene and styrene: synthesis, characterization, and thermal and surface properties

“…Similarly to monouoro-and triuoromethyl groups, the diuoromethyl function (-CF 2 H) is another uorinated alkyl moiety of great interest since it plays critical roles as a lipophilic isostere of hydroxyl group as well as a hydrogen bond donor. [37][38][39] However, synthesis of such molecules is not straightforward as in case of mono-and triuorinated analogues. 40 Therefore, studies on their properties and possible applications seem to be still an unexplored eld, worth to investigate.…”