A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues (1, 2, 6-9, 13-15, and 23) are active in the low nanomolar range (IC(50) <5 nM), very close to the parent compound huprine X. Compounds 2, 6, and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700-1160-fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl-binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines (2, 6, and 7) showed that most of the difference in K(D) is accounted by a decrease in k(on) , which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC(50) =1.1 nM) and showed a rather weak toxicity (LD(50) =40 mg kg(-1) ) and an ability to cross the blood-brain barrier with doses above 15 mg kg(-1).
The Raman spectra of several surfactants such as didodecyldimethylammonium bromide (DDAB), cetyltrimethylammonium bromide (CTAB), dimyristoylphosphatidylcholine (DMPC), cetylpyridinium chloride (CPC), dihexadecyl phosphate (DHP), and sodium laurate (NaL) have been investigated in the solid, multilayer, micellar, and multibilayer forms. The first four are cationic surfactants while DHP and NaL are anionic. Raman spectra show that they all exist in an all-trans configuration in the crystalline state while their structure in the micellar, monolayer, and multibilayer (film) forms is a mixture of gauche and trans configurations. Surface-enhanced Raman scattering (SERS) spectra of the above surfactants (with the exception of CPC) show an unexpected enhancement for C-H stretching modes at potentials more negative than -0.8 V versus the saturated calomel electrode along with the appearance of two new SERS vibration bands at 2710 and 2815 cm -1 . In the multibilayer film, the SERS spectra of some of these surfactants (DDAB, CTAB, DMPC) are dominated by two intense bands located at 1130 cm -1 and 1530 cm -1 . The 1130 cm -1 band corresponds to the all-trans alkyl structure, which is common in the Raman spectra of all of these surfactants, while the 1530 cm -1 band is a totally new band. We associate it with a bending mode of the quaternary nitrogen methyl groups. Ab initio Hartree-Fock/6-311G calculations of CTAB in the trans and gauche configurations are used to support the band assignments.
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