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.

Keywords::

• Anti-HCV evaluation for genotypes 1b and 4a
• conserved binding site’s structures of HCV proteases of genotypes 1b and 4a
• C-Docker molecular modeling
• new anti-HCV prototypes against genotypes 4a and 1b

Acknowledgement

The authors are deeply acknowledging Bahgat M., M., professor of microbiology department of NCR of Egypt, for performing anti-HCV evaluation of genotype 4a. Also, it’s an honor to appreciate Dr. Jeffrey S. Glenn, Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Director, Center for Hepatitis and Liver Tissue Engineering, Stanford University, School of Medicine, Stanford, USA, for her kind collaboration in performing anti-HCV testing of genotype 1b.

Declaration of interest

All the authors have no interest and no personal relationships or financial with any peoples or organizations that could inappropriately influence (bias) their work directly or indirectly, during the subject matter or materials discussed in this manuscript.