کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1397638 | 1501180 | 2011 | 9 صفحه PDF | دانلود رایگان |
This study is focused on a new series of benzylindole derivatives with various substituents at the benzene-fused ring, suggested by our 3D pharmacophore model developed for HIV-1 integrase inhibitors (INIs). All synthesized compounds proved to be active in the nanomolar range (6–35 nM) on the strand-transfer step (ST). In particular, derivative 4-[1-(4-fluorobenzyl)-5,7-dimethoxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (8e), presenting the highest best-fit value on pharmacophore model, showed a potency comparable to that of clinical INSTIs GS 9137 (1) and MK-0518 (2). The binding mode of our molecules has been investigated using the recently published crystal structure of the complex of full-length integrase from the prototype foamy virus in complex with its cognate DNA (PFV-IN/DNA). The results highlighted the ability of derivative 8e to assume the same binding mode of MK-0518 and GS 9137.
A novel series of benzylindole derivatives, suggested by molecular modeling studies, was synthesized and evaluated for their anti-retroviral activity.Figure optionsDownload as PowerPoint slideResearch highlights
► HIV-1 is the etiological agent of Immunodeficiency Acquired Syndrome (AIDS).
► HIV-1-IN plays a key role in stable infection.
► A novel series of benzylindole derivatives was designed and synthesized.
► The strand-transfer IN step was inhibited at nanomolar concentration.
► The key role of some structural requirements for binding between IN and STIs has been demonstrated.
Journal: European Journal of Medicinal Chemistry - Volume 46, Issue 2, February 2011, Pages 756–764