Two series of peptidomimetics containing a novel C2 pseudosymmetrical hydroxyalkyldiamino core structure were prepared from amino acid starting materials and tested for inhibitory activity against the HIV-1 protease (HIV- 1 Pt) 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 (IC50 = 430 nM). The corresponding 2,4-diamino-1-hydroxybutane derivative (6b) was the best inhibitor of the series (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 compounds.
Bibliographical noteFunding Information:
Financial support for this work by Ministero dell' Università e della Ricerca Scientifica e Tecnologica (Cofinanziamento Progetto Chimica dei Composti Organici di Interesse Biologico) is gratefully acknowledged. We warmly thank Prof. Y. Kiso of Kyoto Pharmaceutical University (Department of Medicinal Chemistry) for a kind gift of HIV-1 protease inhibitor, KNI-272.
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- Aspartyl protease
- HIV-1 inhibitors