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A Novel Dipeptide‐based HIV Protease Inhibitor Containing Allophenylnorstatine
Author(s) -
AbdelRahman Hamdy M.,
ElKoussi Nawal A.,
Alkaramany Gamal S.,
Youssef Adel F.,
Kiso Yoshiaki
Publication year - 2004
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200400882
Subject(s) - dipeptide , chemistry , stereochemistry , carboxamide , scissile bond , protease , protease inhibitor (pharmacology) , hiv 1 protease , enzyme inhibitor , amino acid , human immunodeficiency virus (hiv) , enzyme , biochemistry , medicine , family medicine , antiretroviral therapy , viral load
Dipeptide analogues incorporating allophenylnorstatine [Apns; (2S, 3S)‐3amino‐2‐hydroxy‐4‐phenylbutyric acid] as a transition state mimic at the scissile bond were designed and synthesized in the hope of obtaining a novel KNI series of HIV protease inhibitors. The precursors, N‐P 2 ′‐3‐(2S, 3S)‐3‐(tert‐butyloxy‐carbonyl)amino‐2‐hydroxy‐4‐phenylbutanoyl)‐5, 5‐dimethylthiazolidine‐4‐carboxamide (N‐Boc‐Apns‐Dmt‐P 2 ′) 4a – p were prepared by deprotection of the synthones N‐P 2 ′‐(tert‐butyloxycarbonyl)‐5, 5‐dimethylthiazolidine‐4‐carboxamide (Boc‐Dmt‐P 2 ′) 2a – p , then coupling with (2S, 3S)3‐( tert ‐butyloxycarbonyl)amino‐2‐hydroxy‐4‐phenylbutanoic acid (N‐Boc‐Apns‐OH) 3 . The deprotected intermediates 4 were coupled with the activated carboxyl groups of the P 2 ligands to afford the target dipeptides. In this work, we fixed at the P 2 site either a 2, 6‐dimethylphenoxyacetyl or a 3‐hydroxy‐2‐methylbenzoyl group. Substitutes at the P 2 ′ site were varied to afford the members of the series 7 and 8 . Improved activity of most of the members of series 8 relative to their analogues of series 7 can be partially attributed to the differences in the structures of the P 2 moieties. Positional isomerism in the P 2 ′ moieties significantly affected the activity and polarity of the target.