Περίληψη:
Novel symmetric molecules, bearing a benzidine prolinamide core, two terminal carbamate caps of variable sizes and nature, including natural and unnatural amino acids were developed. Several terminal N-carbamate substituents of the core structure, ranging from linear methyl, ethyl and butyl groups to branching isobutyl group; and an aromatic substituent were also synthesized. Series 1 has hydrophobic AA residues, namely S and R phenylglycine and a terminal carbamate capping group, whereas Series 2 bears sulphur containing amino acids, specifically S and R methionine and the natural R methylcysteine. The novel compounds were tested for their inhibitory activity (EC50) and their cytotoxicity (CC50), using an HCV 1b (Con1) reporter replicon cell line. Compound 4 with the unnatural capping residue, bearing D-Phenylglycine amino acid residue and N-isobutyloxycarbonyl capping group, was the most active within the two series, with EC50 = 0.0067 nM. Moreover, it showed high SI50 > 14788524 and was not cytotoxic at the highest tested concentration (100 μΜ), indicating its safety profile. Compound 4 also inhibited HCV genotypes 2a, 3a and 4a. Compared to the clinically approved NS5A inhibitor Daclatasvir, compound 4 shows higher activity against genotypes 1b and 3a, as well as improved safety profile. © 2020 Elsevier Inc.
Λέξεις-κλειδιά:
benzidine derivative; carbamic acid derivative; daclatasvir; dibenzyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; dibenzyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[3 (methylthio) 1 oxopropane 2,1 diyl]]dicarbamate; dibenzyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; dibenzyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; dibenzyl[[[[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; dibutyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; dibutyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[3 (methylthio) 1 oxopropane 2,1 diyl]]dicarbamate; dibutyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; dibutyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; dibutyl[[[[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; diethyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; diethyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[3 (methylthio) 1 oxopropane 2,1 diyl]]dicarbamate; diethyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; diethyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; diethyl[[[[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; diisobutyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; diisobutyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[3 (methylthio) 1 oxopropane 2,1 diyl]]dicarbamate; diisobutyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; diisobutyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; diisobutyl[[[[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; dimethyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; dimethyl[[ 2,2' [[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[3 (methylthio) 1 oxopropane 2,1 diyl]]dicarbamate; dimethyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis(2 oxo 1 phenylethane 2,1 diyl)]dicarbamate; dimethyl[[[[(1,1' biphenyl) 4,4' diylbis (azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; dimethyl[[[[(1,1' biphenyl) 4,4' diylbis(azanediyl)]bis(carbonyl)]bis(pyrrolidine 2,1 diyl)]bis[4 (methylthio) 1 oxobutane 1,2 diyl]]dicarbamate; nonstructural protein 5A inhibitor; unclassified drug; amino acid; antivirus agent; benzidine; benzidine derivative; carbamic acid derivative; virus RNA, antiviral activity; Article; carbon nuclear magnetic resonance; CC50 (cytotoxic concentration); comparative study; controlled study; cytotoxicity assay; drug synthesis; EC50; Huh-7 cell line; human; human cell; hydrogen bond; hydrophobicity; immunofluorescence; liquid chromatography-mass spectrometry; mass spectrometry; molecular weight; nonhuman; priority journal; proton nuclear magnetic resonance; RNA extraction; RNA replication; stereochemistry; cell culture; chemical structure; chemistry; dose response; drug effect; Hepacivirus; microbial sensitivity test; stereoisomerism; structure activity relation; synthesis, Amino Acids; Antiviral Agents; Benzidines; Carbamates; Cells, Cultured; Dose-Response Relationship, Drug; Hepacivirus; Humans; Microbial Sensitivity Tests; Molecular Structure; RNA, Viral; Stereoisomerism; Structure-Activity Relationship
