設計合成與評估8-甲氧基喹啉衍生物作爲抗阿茲海默症之潛在多靶點藥物

Abstract

The aim of this thesis is to design and synthesize novel series of 8-methoxyquinoline derivatives based on lead compound J2326, which targets and modulates multiple facets of Alzheimer’s disease (AD). The J2326 was designed and synthesized previously in our lab by merging two compounds, namely neurotrophic n-hexacosanol and metal-chelating clioquinol, which blocked metal-induced fAβ formation. A series of 8-methoxyquinoline-2-yl-alkyl derivatives was designed by introduction of hydroxyl, carbonyl, oxime moieties at α position on the side chain of J2326 to improve its solubility and metal chelation activity profile. Benzylic oxidation of appropriate 8-methoxy-2-methylquinoline afforded respective 8-methoxy-2-aldehyde-quinoline, which on Grignard reaction with dec-9-en-1-ylmagnesium bromide afforded corresponding alkene-alcohol, with side chain bearing terminal olefin. This terminal olefin was then converted to hydroxyl group by hydroboration oxidation reaction to afford first series of target molecules (TM). Further, the α-hydroxyl moiety of these molecules was converted to carbonyl by selective oxidation of secondary alcohol to afford second series of TM. These ketones were then converted to oximes by reaction with hydroxylamine hydrochloride to afford third series of TM. The biological evaluation of these 8-methoxyquinoline derivatives demonstrated that all compounds retained metal chelating as well as neurotrophic activities as that of J2326. Among these, compounds with oxime and secondary alcohol at α position were found better than carbonyl for anti-fAβ and neurotrophic activities. Structure-activity relationship (SAR) study led to identification of novel leads oxime 6c， 6d and 6f with 5’-F, 5’-CF3 and 6’-F substituted which were more effective than J2326. Interestingly, most compounds have much better solubility profile (0.6-87.7μg/ml) than J2326 (<0.003 μg/ml). Furthermore, these compounds showed anti-ROS activity and acceptable blood-brain barrier permeability profile. Compound 6c, 6d, 6f and 6h can serve as leads for further optimization to develop a potential candidates for AD treatment.