Synthesis and biological evaluation of the first N-alkyl cage dimeric 4-aryl-1,4-dihydropyridines as novel nonpeptidic HIV-1 protease inhibitors.
A first series of novel NH and N-alkyl-substituted cage dimeric 4-aryl-1,4-dihydropyridines 3a-f has been synthesized and evaluated as HIV-1 protease inhibitors in in vitro assays. While the NH and N-methyl derivatives 3a,b,e,f were almost inactive with IC(50) values of about 200 microM, the N-Benzyl compounds exhibited stronger activity with an IC(50) value of 16.2 microM for the presently best compound 3c. The type of HIV-1 protease inhibition of these novel inhibitors was characterized as competitive. With the increase of observed activity from NH and N-methyl derivatives to N-benzyl compounds, respectively, the binding mode may correspond to that of cyclic and azacyclic ureas showing hydrophobic interactions of the four aromatic residues to the S1/S1' and S2/S2' regions of HIV-1 protease.
Hilgeroth
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Department of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle, Germany.
Wiese
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Billich
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D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry; D019281:Dimerization; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015497:HIV-1; D013329:Structure-Activity Relationship
D004095:Dihydropyridines; D017320:HIV Protease Inhibitors