A series of novel HIV‐1 protease inhibitors based on the (hydroxyethylamino)‐sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P2 ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the ‐CH2‐ of P1‐P2 linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P1′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV‐1 protease with an IC50 value of 5 nm, also exhibited good anti‐SIV activity (EC50 = 0.8 μm) with low toxicity (TC50 > 100 μm). The flexible docking of inhibitor 23 to HIV‐1 protease active site rationalized the interactions with protease.
The title compounds, labeled both with deuterium and with carbon-14, have been subjected to nitrous acid deamination in acetic acid-sodium acetate solution. The yields of products have been determined by gpc, by isotope dilution, by liquid column chromatography, or by all three methods. The mechanistic implications of the data-namely that the "memory effects'' can be explained by counterion control and that the classical carbonium ion intermediates survive several 1,2 shifts-are discussed in detail. It is concluded either that "hot" carbonium ions are not necessary to explain the results, or that they must be redefined. a multiplicity of products (by comparison with the corresponding solvolyses). By definition,7 then, "hot" carbonium ions should have "lost most if not all of their sizzle"8 after a single hydride shift or Wagner-Meerwein rearrangement.
Die Desaminierung von 3-endo-Hydroxy-3-phenyl-2-endo-bicyclo[2.2.1]heptylamin (4) in EssigsaureINatriumacetat ergibt A3-Cyclohexenyl-phenyl-keton (7) und die Monoacetate der Diole 2-exo-7-anti-Dihydroxy-7-phenyI-bicyclo[2.2.1]heptan (5) und cis-2.6-Dihydroxy-6-exo-phenyl-hicyclo[3. I . Ilheptan (6) sowie fun€ andere Produkte. Die Wiederholung der Desaminierung mit Aminen, die Deuterium in der exo-5.6-Stellung (4a) und in der exo-2-Stellung (4c) enthalten, ergibt neben den ublichen Reaktionsprodukten Aj-Cyclohexenyl- Deamination of 3-endo-hydroxy-3-phenyl-2-endo-bicyclo[2,2,l]heptylamine (4) in acetic acid/ sodium acetate leads to A3-cyclohexenyl phenyl ketone (7) and monoacetates of the two diols 2-exo-7-anti-dihydroxy-7-phenylbicyclo [2,2,1 Iheptane (5) and cis-2,6-dihydroxy-6-exo-phenylbicyclo[3,1,l]heptane (6) plus five other products. Repetition of the deamination with amine containing deuterium in the exo-5,6-positions (4a) and in the exo-2-position (4c) leads to the usual products plus the following respective fractions : 1) A3-cyclohexenyl-5,6-d2 phenyl ketone (7a) and 2) As-cyclohexenyl-4-d phenyl ketone (7c) containing a small proportion of A3-cyclohexenyl-3-d phenyl ketone (7d). The formation of 7d is evidence for the transformation G + 7 similar to the transformation of the piny1 ion D to a-terpineol (3).
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