کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5216713 | 1383274 | 2014 | 11 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Structural optimization of cyclic sulfonamide based novel HIV-1 protease inhibitors to picomolar affinities guided by X-ray crystallographic analysis Structural optimization of cyclic sulfonamide based novel HIV-1 protease inhibitors to picomolar affinities guided by X-ray crystallographic analysis](/preview/png/5216713.png)
Synthesis and HIV-1 protease inhibitory activity of compound 5 based on the structure of a novel cyclic sulfonamide pharmacophore has been recently disclosed from our group. X-ray crystallographic structure of 5 when bound to the HIV-1 protease defined its binding mode. The importance of the geometry of the substitution at C4-Me (S configuration) was emphasized. In the present paper we wish to disclose the design of novel inhibitors 47 and 48 based on the X-ray structure of compound 5 bound to the HIV-1 protease, their synthesis and activity against HIV-1 protease. By making changes at the C4 position and the carbamate linkage the above compounds 47 and 48 were found to be approximately one hundred fold more active compared to 5 and their Ki values are in the picomolar range. An unusual observation regarding the activity and geometry was made with compounds 51 and 52. X-ray results demonstrate that 48 and 52 bind to the same binding pocket with simultaneous change in the conformation of the cyclic sulfonamide ring.
Journal: Tetrahedron - Volume 70, Issue 18, 6 May 2014, Pages 2894-2904