title: Ligand design, synthesis and biological anti-HCV evaluations for genotypes 1b and 4a of certain 4-(3- & 4-[3-(3,5-dibromo-4-hydroxyphenyl)-propylamino]phenyl) butyric acids and 3-(3,5-dibromo-4-hydroxyphenyl)-propylamino-acetamidobenzoic acid esters.
abstract: 4-(4-[N-1-carboxy-3-(3,5-dibromo-4-hydroxyphenyl)-3-oxo-propylamino]phenyl)-4-oxo-butyric acid (V), 4-(3- & 4-[N-1-carboxy-3-(3,5-dibromo-4-hydroxyphenyl)-3-oxo-propylaminophenyl]-2-aryl-4-oxo-butyric acids (Xa-e) and 4-(2-alkyl-2-[N-3-(3,5-dibromo-4-hydroxyphenyl)-1-carboxy-3-oxo-propylamino]acetamido) benzoate esters (XVa-e) were designed, synthesized and biologically evaluated as anti-HCV for genotypes 1b and 4a. The design was based on their docking scores with HCV NS3/4A protease-binding site of the genotype 1b (1W3C), which is conserved in the genotype 4a structure. The docking scores predicted that most of these molecules have higher affinity to the HCV NS3/4A enzyme more than Indoline lead. These compounds were synthesized and evaluated for their cytopathic inhibitory activity against RAW HCV cell cultures of genotype 4a and also examined against Huh 5-2 HCV cell culture of genotype 1b, utilizing Luciferase and MTS assays. Compounds Xa and Xb have 95 and 80% of the activity of Ribavirin against genotype 4a and compounds XVa, XVb and XVd exerted high percentage inhibitory activity against genotype 1b equal 87.7, 84.3 and 82.8%, respectively, with low EC50 doses.
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University , 11655 El khalifa El Mamoon Street, Abbassia, Cairo , Egypt.
authors.forename: Mohamed Abdel Hamid
authors.initials: MA
authors.lastname: Ismail
authors.forename: Khaled A M
authors.initials: KA
authors.lastname: Abouzid
authors.forename: Nasser Saad
authors.initials: NS
authors.lastname: Mohamed
authors.forename: Eman Mahmoud Elawady
authors.initials: EM
authors.lastname: Dokla
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D011437:Propylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000589135:3-(3,5-dibromo-4-hydroxyphenyl)-propylamino-acetamidobenzoic acid; C000589133:4-(3-(3-(3,5-4-(3-(3-(3,5-dibromo-4-hydroxyphenyl)-propylamino)phenyl)butyric acid; D000998:Antiviral Agents; D002087:Butyrates; D004952:Esters; D008024:Ligands; D011437:Propylamines; D062366:para-Aminobenzoates