1601490-08-7Relevant articles and documents
Structural optimization of cyclic sulfonamide based novel HIV-1 protease inhibitors to picomolar affinities guided by X-ray crystallographic analysis
Ganguly, Ashit K.,Alluri, Sesha S.,Wang, Chih-Hung,Antropow, Alyssa,White, Alex,Caroccia, Danielle,Biswas, Dipshikha,Kang, Eunhee,Zhang, Li-Kang,Carroll, Steven S.,Burlein, Christine,Fay, John,Orth, Peter,Strickland, Corey
, p. 2894 - 2904 (2014/04/17)
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.
