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- Bäckbro, Kristina, et al.
(author)
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Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor
- 1997
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 898-902
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Journal article (peer-reviewed)abstract
- Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 Å resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.
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- Cerecetto, H, et al.
(author)
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1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs : structure-activity relationships.
- 1999
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 42:11, s. 1941-50
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Journal article (peer-reviewed)abstract
- The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.
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- Hultén, Johan, et al.
(author)
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Cyclic HIV-1 protease inhibitors derived from mannitol : synthesis, inhibitory potencies, and computational predictions of binding affinities
- 1997
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 885-897
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Journal article (peer-reviewed)abstract
- Ten C-2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (la and 2-5). Thirdly, compounds with hydrogen bond-accepting or -donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
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