当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Structure based medicinal chemistry approach to develop 4-methyl-7-deazaadenine carbocyclic nucleosides as anti-HCV agent.

Structure based medicinal chemistry approach to develop 4-methyl-7-deazaadenine carbocyclic nucleosides as anti-HCV agent.

Abstract：

: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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Thiyagarajan A,Salim MT,Balaraju T,Bal C,Baba M,Sharon A

doi

10.1016/j.bmcl.2012.09.072

subject

Has Abstract

pub_date

2012-12-15 00:00:00

pages

7742-7

issue

24

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(12)01227-9

journal_volume

22

pub_type

杂志文章

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