Novel 3-(2-Adamantyl)pyrrolidines with potent activity against influenza A virus—identification of aminoadamantane derivatives bearing two pharmacophoric amine groups

• Published in: Bioorganic & medicinal chemistry letters 2001-08, Vol.11 (16), p.2137-2142
• Main Authors: Stamatiou, George, Kolocouris, Antonios, Kolocouris, Nicolas, Fytas, George, Foscolos, George B, Neyts, Johan, De Clercq, Erik
• Format: Article
• Language: English
• Subjects: Amantadine - chemistry; Amines - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Influenza A virus - drug effects; Medical sciences; Microbial Sensitivity Tests; Molecular Conformation; Pharmacology. Drug treatments; Pyrrolidines - chemistry; Pyrrolidines - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00388-2

The 3-(2-adamantyl)pyrrolidines 8a– g, 14 were synthesized and evaluated for activity against influenza A virus. The parent N–H compound 14 was several times more active than amantadine against H 2N 2 and H 3N 2 influenza A virus. The combined use of NMR spectroscopy and computational chemistry showed that the conformation around the pyrrolidine–adamantyl carbon–carbon bond is trans and the pyrrolidine heterocycle has an envelope conformation with C-2 out of the plane of the other ring atoms. N-Dialkylaminoethyl substitution of compound 14 resulted in the potent diamine analogues 8e, f, g. Interestingly, their lactam amine precursors were also active. Compounds 8e, f, g are the first adamantane derivatives, bearing two amine groups, reported to be active against influenza A virus. Pyrrolidines 14, 8a, e, g were synthesized and found active against H 2N 2 and H 3N 2 influenza A virus. Through a combination of NMR spectroscopy and molecular mechanics calculations it was shown that the parent 3-(2-adamantyl)pyrrolidine 14 adopts a trans conformation around C3–C2′ bond and an E(2) pyrrolidine conformation. Compounds 8e, g are the first adamantane derivatives, bearing two amine groups, reported to be active against influenza A virus.