NaBH<sub>4</sub>, CH<sub>3</sub>CO<sub>2</sub>H, Pd/C has been described as an effective reagent system to hydrogenate alkenes. Here, we show that the hydrogenation occurs chemosele...NaBH<sub>4</sub>, CH<sub>3</sub>CO<sub>2</sub>H, Pd/C has been described as an effective reagent system to hydrogenate alkenes. Here, we show that the hydrogenation occurs chemoselectively, making it possible to hydrogenate alkenes under Pd/C catalysis with hydrogen created in situ without O- or N-debenzylation.展开更多
The c-Jun N-terminal kinase （JNK） is involved in a variety of important cellular processes and aberrant JNK activity is associated with many human diseases.The ligand-based and receptor-based alignment rules were us...The c-Jun N-terminal kinase （JNK） is involved in a variety of important cellular processes and aberrant JNK activity is associated with many human diseases.The ligand-based and receptor-based alignment rules were used to build 3D-QSAR models for a series of N-benzyl isatin oximes JNK inhibitors. The best models were obtained for the receptor-based alignment with CoMSIA combining steric （S）, electrostatic （E）, and hydrogen bond donor （D） and hydrogen bond acceptor （A） fields （q2 = 0.759, r2 = 0.966, r2 pred = 0.703）. Based on the contour maps of RB CoMSIA model, some key structural factors responsible for inhibitory activity were investigated. Large groups at N-substituent or R6 position are preferred to interact with hydrophobic residues Ile70, Asp150, Ala151, Asn152 and Ser193. Electron-donating or hydrogen bond donor groups on the isatin ring would form polar and hydrogen bond with the negative-charged residue Glu147. In addition, electron-withdrawing groups or hydrogen bond acceptor group near the N-substituent would enhance inhibitory activity. The results are in good accordance and complementary to each other. The developed models could provide guidance in the rational design of more potent and selective JNK inhibitors.展开更多
Current drugs for treating human cytomegalovirus(HCMV)infections are limited by resistance and treatment-associated toxicities.In developing mechanistically novel HCMV antivirals,we discovered an N-benzyl hydroxypyrid...Current drugs for treating human cytomegalovirus(HCMV)infections are limited by resistance and treatment-associated toxicities.In developing mechanistically novel HCMV antivirals,we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit(8a)inhibiting HCMV in submicromolar range.We describe herein the structure–activity relationship(SAR)for 8a,and the characterization of potent analogs for cytotoxicity/cytostatic property,the preliminary mechanism of action,and the absorption,distribution,metabolism and excretion(ADME)properties.The SAR revealed a few pharmacophore features conferring optimal antiviral profile,including the 5-OH,the N-1 benzyl,at least one–CH_(2)−in the linker,and a di-halogen substituted phenyl ring in the amide moiety.In the end,we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index.The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay,a virus entry assay,a time-of-addition assay,and a compound withdrawal assay.ADME profiling measuring aqueous solubility,plasma and liver microsomal stability,and parallel artificial membrane permeability assay(PAMPA)permeability demonstrated largely favorable drug-like properties.Together,these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.展开更多
文摘NaBH<sub>4</sub>, CH<sub>3</sub>CO<sub>2</sub>H, Pd/C has been described as an effective reagent system to hydrogenate alkenes. Here, we show that the hydrogenation occurs chemoselectively, making it possible to hydrogenate alkenes under Pd/C catalysis with hydrogen created in situ without O- or N-debenzylation.
基金supported by the Beijing Natural Science Foundation(Grant No.2123062)Research Fund for the Doctoral Program of Higher Education of China(Grant No.20121103120008)Science and Tech-nology Foundation of Beijing University of Technology(Grant No.ykj-2012-8725)
文摘The c-Jun N-terminal kinase （JNK） is involved in a variety of important cellular processes and aberrant JNK activity is associated with many human diseases.The ligand-based and receptor-based alignment rules were used to build 3D-QSAR models for a series of N-benzyl isatin oximes JNK inhibitors. The best models were obtained for the receptor-based alignment with CoMSIA combining steric （S）, electrostatic （E）, and hydrogen bond donor （D） and hydrogen bond acceptor （A） fields （q2 = 0.759, r2 = 0.966, r2 pred = 0.703）. Based on the contour maps of RB CoMSIA model, some key structural factors responsible for inhibitory activity were investigated. Large groups at N-substituent or R6 position are preferred to interact with hydrophobic residues Ile70, Asp150, Ala151, Asn152 and Ser193. Electron-donating or hydrogen bond donor groups on the isatin ring would form polar and hydrogen bond with the negative-charged residue Glu147. In addition, electron-withdrawing groups or hydrogen bond acceptor group near the N-substituent would enhance inhibitory activity. The results are in good accordance and complementary to each other. The developed models could provide guidance in the rational design of more potent and selective JNK inhibitors.
基金This research was supported by the National Institute of Allergy and Infectious Diseases,the National Institutes of Health,United States grant number R01AI136982(to Robert J.Geraghty and Zhengqiang Wang,USA).
文摘Current drugs for treating human cytomegalovirus(HCMV)infections are limited by resistance and treatment-associated toxicities.In developing mechanistically novel HCMV antivirals,we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit(8a)inhibiting HCMV in submicromolar range.We describe herein the structure–activity relationship(SAR)for 8a,and the characterization of potent analogs for cytotoxicity/cytostatic property,the preliminary mechanism of action,and the absorption,distribution,metabolism and excretion(ADME)properties.The SAR revealed a few pharmacophore features conferring optimal antiviral profile,including the 5-OH,the N-1 benzyl,at least one–CH_(2)−in the linker,and a di-halogen substituted phenyl ring in the amide moiety.In the end,we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index.The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay,a virus entry assay,a time-of-addition assay,and a compound withdrawal assay.ADME profiling measuring aqueous solubility,plasma and liver microsomal stability,and parallel artificial membrane permeability assay(PAMPA)permeability demonstrated largely favorable drug-like properties.Together,these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.
