Syntheses and neuraminidase inhibitory activity of multisubstituted cyclopentane amide derivatives.
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| Abstract |
In further studies aimed toward identifying effective and safe inhibitors of influenza neuraminidases, we synthesized a series of multisubstituted cyclopentane amide derivatives. Amides prepared were 14 examples of N-substituted alkyl or aralkyl types from primary amines, 13 examples of the N,N-disubstituted alkyl, aralkyl, or substituted-alkyl type from secondary amines, and 12 examples from cycloaliphatic or substituted cycloaliphatic secondary amines. These compounds bearing two chiral centers, at position-1 in the ring and position-1' in the side chain attached at position 3, were tested for their ability to inhibit A and B forms of influenza neuraminidase. The 1-ethylpropylamide, diethylamide, dipropylamide, and 4-morpholinylamide showed very good inhibitory activity (IC(50) = 0.015-0.080 microM) vs the neuraminidase A form, but modest activity (IC(50) = 3.0-9.2 microM) vs the neuraminidase B form. Since the parent amides bear two chiral centers (C-1 and C-1'), three of the better inhibitors were tested at higher levels of diastereomeric purity. The diastereomers corresponding to the active forms of the 1-(ethyl)propylamide, the diethylamide, and the dipropylamide (all of the same configuration at the C-1' chiral center), and the diastereomer of the diethylamide representing the active form at both C-1' and C-1 were isolated or synthesized from precursors that were isolated as diastereomers. These diastereomers showed some improvement in neuraminidase inhibition over the parent diastereomeric mixtures. 1-Carboxy-1-hydroxy derivatives of the best active compounds, the diethylamide and the dipropylamide, were also prepared. These compounds were not as active as the compounds without the 1-hydroxy group. In an in vivo study, the C-1' active isomer of the diethylamide from the 1-carboxy series was tested in influenza-infected mice by oral and intranasal administration and found to be very effective only intranasally in preventing weight loss at doses as low as 0.1 (mg/kg)/day.
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| Authors | Pooran Chand, Y Sudhakar Babu, Shanta Bantia, Scott Rowland, Ali Dehghani, Pravin L Kotian, Tracy L Hutchison, Shoukath Ali, Wayne Brouillette, Yahya El-Kattan, Tsu-Hsing Lin |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 8 Pg. 1919-29 (Apr 08 2004) ISSN: 0022-2623 [Print] United States |
| PMID | 15055992 (Publication Type: Journal Article) |
| Chemical References |
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