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 hydroxyalkyldiamino core structure were prepared from amino acid starting materials and tested for inhibitory activity against the HIV-1 protease (HIV-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, displayed modest HIV-1 Pr inhibition (IC(50) = 430 nM). The corresponding 2,4-diamino-1-hydroxybutane derivative (6b) was the best inhibitor of the series (IC(50) = 160 nM). Interestingly, 6a and 6b showed satisfactory inhibition of HIV replication in cell culture (ED(50) = 340 and 110 nM, respectively), a result which suggests good cell membrane penetration by this class of compounds.
Department of Pharmaceutical Sciences and Biotecnology Centre, University of Ferrara, Ferrara, Italy.
M
M
Marastoni
M
M
Bazzaro
F
F
Bortolotti
S
S
Salvadori
R
R
Tomatis
D000215:Acylation; D000440:Butanols / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D011407:Propane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000440:Butanols; D017320:HIV Protease Inhibitors; D016333:HIV Protease; D011407:Propane