Structural optimization of cyclic sulfonamide based novel HIV-1 protease inhibitors to picomolar affinities guided by X-ray crystallographic analysis

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 K_i 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.