Wang, Shenfeng published the artcile2-aryl-3-carbonylquinolones: design, synthesis and biological evaluation of novel HCV NS5B polymerase inhibitors, Safety of Ethyl 3-(dimethylamino)acrylate, the publication is Huaxue Xuebao (2014), 72(8), 906-913, database is CAplus.
Hepatitis C virus (HCV) infection is a global health problem that impacts approx. 180 million individuals. Until recently the current therapy for treating HCV infection has been regular injections of pegylated α-interferon (PEG-IFN) with daily oral administration of ribavirin (RBV). However, PEG-IFN/RBV treatment is only effective for only 50% of genotype 1 patients and associated with significant adverse effects including fatigue, hemolytic anemia, depression, and flulike symptoms. Therefore, the search for direct acting antivirals (DAAs) that are safe and effective has become an urgent endeavor. HCV NS5B polymerase, an essential enzyme for the HCV RNA replication, has emerged as an attractive and validated target for the direct HCV therapeutic intervention. Since NS5B polymerase needs a divalent metal ion as a cofactor in the active site for its catalytic function, the metal chelation motif-containing quinolone-3-carboxylic scaffold has been explored as a new class of non-nucleoside NS5B inhibitors. Two groups have recently reported a preliminary structure-activity relationship (SAR) study on the 4-quinolone-3-carboxylic acids as HCV NS5B inhibitors, just focused on the N-1, C-3 and C-6/7 substitutions. Based on the binding mode revealed by the cocrystal structure of the quinolone inhibitor bound to the NS5B enzyme, for the first time we proposed to introduce a hydrophobic group at C-2 position on the quinolone ring to improve the anti-HCV potency. By making use of the new method to synthesize 2-substituted quinolone-3-carboxylic acid derivatives recently developed by our group, we conducted a comprehensive SAR study on the 2-aryl-3-carbonylquinolone-based non-nucleoside inhibitors of HCV NS5B polymerase. Starting from the readily accessible amides and 3-oxo-3-arylpropanoates, structurally diverse 2-substituted quinolone-3-carboxylic acid derivatives were efficiently furnished by a tandem addition-elimination reaction/nucleophilic aromatic substitution reaction via an imine-enamine intermediate. The anti-HCV potency and cytotoxicity were evaluated in the HCV-infected host cells Huh7.5.1 assay system. To our delight, the incorporation of a hydrophobic aryl group into 2-position of the quinolone core really enhanced the inhibitory activity against the HCV replication in the host cells with a 2-fold selectivity over the cytotoxicity. Meanwhile, a small size hydrophobic group at N-1 position was favored for the 2-arylquinolone-derived NS5B inhibitors. Further structural variation was investigated on the C-3 and C-7 substituents, with an aromatic ester and an N-Me piperazine being an optimal moiety, resp. The global structural optimization at positions N-1, C-2, C-3 and C-7 resulted in the discovery of novel 2-aryl substituted quinolone inhibitors with low micromolar EC50 values to inhibit the replication of the HCV RNA in the host cell Huh7.5.1 and therapeutic indexes of 2∼6, providing a new promising lead for the further development into anti-HCV drug candidates.
Huaxue Xuebao published new progress about 924-99-2. 924-99-2 belongs to esters-buliding-blocks, auxiliary class Alkenyl,Amine,Aliphatic hydrocarbon chain,Ester, name is Ethyl 3-(dimethylamino)acrylate, and the molecular formula is C9H7NO2, Safety of Ethyl 3-(dimethylamino)acrylate.
Referemce:
https://en.wikipedia.org/wiki/Ester,
Ester – an overview | ScienceDirect Topics