Symmetry-based inhibitors of HIV-1 protease. Design, synthesis and preliminary structure-activity studies of acylated 2,3-diamino-1-hydroxypropanes and 2,4 diamino-1-hydroxybutanes

Two series of peptidomimetics containing a novel C-2 pseudosymmetrical hydr oxyalkyldiamino core structure were prepared from amino acid starting mater ials and tested for inhibitory activity against the HIV-1 protease (HN-1 Pr ) and the virus in cell culture. In the 2,3-diamino-1-hydroxypropane series , compound 6a, containing P1/P1(I) benzyl and P2/P2(I) Fmoc substituents, d isplayed modest HTV-1 Pr inhibition (IC50 = 430 nM). The corresponding 2,4- diamino-1-hydroxybutane derivative (6b) was the best inhibitor of the serie s (IC50 = 160 nM). Interestingly, 6a and 6b showed satisfactory inhibition of HIV replication in cell culture (ED50 = 340 and 110 nM, respectively), a result which suggests good cell membrane penetration by this class of comp ounds. (C) 1999 editions scientifiques et medicales Elsevier SAS.