A novel dipeptide-based HIV protease inhibitor containing allophenylnorstatine.
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-P2'-3-(2S,3S)-3-(tert-butyloxy-carbonyl)amino-2-hydroxy-4-phenylbutanoyl)-5,5-dimethylthiazolidine-4-carboxamide (N-Boc-Apns-Dmt-P2') 4a-p were prepared by deprotection of the synthones N-P2'-(tert-butyloxycarbonyl)-5,5-dimethylthiazolidine-4-carboxamide (Boc-Dmt-P2') 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 P2 ligands to afford the target dipeptides. In this work, we fixed at the P2 site either a 2,6-dimethylphenoxyacetyl or a 3-hydroxy-2-methylbenzoyl group. Substitutes at the P2' 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 P2 moieties. Positional isomerism in the P2' moieties significantly affected the activity and polarity of the target.
Abdel-Rahman
Hamdy M
HM
Pharmaceutical Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
el-Koussi
Nawal A
NA
Alkaramany
Gamal S
GS
Youssef
Adel F
AF
Kiso
Yoshiaki
Y
D002851:Chromatography, High Pressure Liquid; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D010654:Phenylbutyrates / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid