ABSTRACT
The present study includes the exploration of new possible nucleoside mimetics based on 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine carbocyclic nucleosides (4a-g), which were synthesized by 10-15 synthetic steps and characterized adequately. We report the anti-HCV activities and cytotoxicities of 4a-g. Compound 4a was analyzed by single crystal X-ray diffraction which showed some puckering in the cyclopentene ring with a 2'-endo conformation and anti-base disposition (χ = -125.7°).
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Pyrimidine Nucleosides/chemical synthesis , Antiviral Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Pyrimidine Nucleosides/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacologyABSTRACT
Computer-aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti-hepatitisâ C virus (HCV) agents. Conformational analyses were carried out on 6-amino-1H-pyrazolo[3,4-d]pyrimidine (6-APP)-based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA-dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6-APP analogues were prepared and evaluated for anti-HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC50 value of 6.6â µM as a preliminary anti-HCV lead.
Subject(s)
Antiviral Agents/chemical synthesis , Nucleosides/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Catalytic Domain , DNA-Directed RNA Polymerases/chemistry , DNA-Directed RNA Polymerases/metabolism , Hepacivirus/drug effects , Hepacivirus/metabolism , Humans , Hydrogen Bonding , Molecular Conformation , Molecular Docking Simulation , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Pyrazoles/chemistry , Pyrimidines/chemistry , Virus Replication/drug effectsABSTRACT
The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure-activity relationships of previously discovered molecules (types I, II, III) were analyzed to design new molecules (type IV) by bioisosteric replacement of the amino group. The ligand conformation, binding mode studies and drug like properties were major determinant for selection of molecules for final synthesis. The replacement of amino group with methyl restored the interactions with RNA-template (Tem 799) through bifurcated weak H-bond (C-H...O). This is an interesting finding observed from molecular modeling studies. It was found that 6c-e has anti-HCV activity (EC(50) in 37-46 µM) while 6a, 6b and 6g were inactive. The compound 6f (EC(50) 28 µM) was the most active among the series however it also showed some cytotoxicity (CC(50) 52.8 µM). Except 6f, none of the compounds were found to be cytotoxic (CC(50)>100 µM). The present study discloses structure-based approach for novel anti-HCV lead discovery and opens a future scope of lead optimization.
