TY - JOUR
TI - Symmetric benzidine derivatives as anti-HCV agents: Insight into the nature, stereochemistry of the capping amino acid and the size of the terminal capping carbamates
AU - Abdel Karim, S.E.
AU - Youssef, Y.H.
AU - Abdel-Halim, M.
AU - Frakolaki, E.
AU - Vassilaki, N.
AU - Zoidis, G.
AU - Ahmed, N.S.
AU - Abadi, A.H.
JO - Bioorganic Chemistry
PY - 2020
VL - 102
TODO - null
SP - null
PB - Academic Press Inc.
SN - 0045-2068, 1090-2120
TODO - 10.1016/j.bioorg.2020.104089
TODO - 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
TODO - 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.
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