الفهرس 
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Abstract
Thiazole heterocycle represents the core pharmacophore of several bioactive compounds. Thiazole-based were reported to exhibit marked activities for improving the symptoms of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD). To date, there is no radical cure for NDs, the available drugs only offer symptomatic relief without the ability of slowing down disease progression. Acetylcholinesterase (AChE) is the main target of the currently-available anti-Alzheimer’s drugs. Based on the reported AChE inhibitory activity of several thiazole-based derivatives, new series of thiazole derivatives were have been synthesized as potential AChE inhibitors. In order to obtain the target compounds, the following routes were adopted : 1. The required precursors 4-arylthiazol-2-amines 106a and 106b were prepared via condensation of thiourea and the appropriate aryl methyl ketone in the presence of iodine. 2. The reaction of compounds 106a and 106b with chloroacetyl chloride and triethylamine in chloroform at room temperature yielded the corresponding 2-chloro-N-thiazolyl acetamide derivatives 108a and 108b, which were reacted with ammonium thiocyanate to yield the corresponding dihydrothiazol-4-one analogues 109a and 109b, respectively. 3. Compounds 109a and 109b were condensed with various aromatic aldehydes in the presence of sodium hydroxide to yield the corresponding 5-arylidene derivatives 110a-l, and compound 109b was condensed with 5-methoxyindoline-2,3-dione in acetic acid in the presence of sodium acetate to yield compound 112 (Scheme 1). 4. The aminothiazole derivatives 106a and 106b were reacted with ethyl or benzyl isothiocyanate in N,N-dimethylformamide (DMF) to yield the corresponding thiourea derivatives 113a-d. 5. The thiourea derivatives 113a-d were then reacted with chloroacetic acid in the presence of sodium acetate to yield the thiazolidin-4-one derivatives 114a-d. The reaction of compound 114d with 3,4-dimethoxybenzaldehyde or 2,4-dichlorobenzaldehyde in ethanol, in the presence of catalytic amount of piperidine yielded the corresponding 5-arylidene analogues 115a and 115b, respectively (Scheme 2). 6. 3,4,5-Trimethoxybenzaldehyde 116 was reacted with cyclohexanone 117 (molar ratio 2:1) in ethanolic sodium hydroxide solution to yield the target intermediate α,β-unsaturated ketones 2,6-bis(3,4,5-trimethoxybenzylidene)-cyclohexanone 118. 7. The α,β-unsaturated ketones 118 reacted with the 1,3-disubstituted thiourea derivative 113d via prolonged heating in acetic acid to yield the target 3,4,5,6,7,8-hexahydro-quinazoline-2(1H)-thione 119 (Scheme 3). The purity of the newly synthesized target compounds was checked by thin layer chromatography (TLC), and the structures of these compounds were confirmed by 1H NMR, 13C NMR and Electron Impact (EI-MS) Mass Spectra. The synthesis of the target new compounds necessitated the preparation of the following unavailable starting compounds guided with the published literature : 1. 4-(p-Tolyl)thiazol-2-amine 106a. 2. 4-(p-Methoxyphenyl)thiazol-2-amine 106b. 3. 2-Chloro-N-[(p-tolyl))thiazol-4-yl]acetamide 108a. 4. 2-Chloro-N-[(p-methoxyphenyl))thiazol-4-yl]acetamide 108b. 5. 2-{[(p-Toly)thiazol-2-yl]amino}-4,5-dihydrothiazol-4-one 109a. 6. 2-{[(p-methoxyphenyl)thiazol-2-yl]amino}-4,5-dihydrothiazol-4-one 109b. 7. 1-Benzyl-3-[4-(p-tolylthiazol-2-yl)]thiourea 113b. 8. (2E,6E)-2,6-Bis(3,4,5-trimethoxybenzylidene)cyclohexanone 118. All the newly synthesized compounds 110a-l, 112, 114a-d, 115a, 115b and 119 were tested for in vitro AChE inhibitory activity and their relative AChE inhibitory potency to the currently-used AChE drug donepezil hydrochloride was calculated. Molecular docking analysis of the active compounds was performed in order to predict structural insights regarding the binding interactions, affinities and orientations of these compounds within the AChE active site. The optimum AChE inhibitory activity was attained by compounds 110b and 110g with IC50 values of 103.24 nM and 108.94 nM, respectively, and relative potencies of more than 50%. Compounds 110d, 110h, 110i, 110l, 112, 114d, 115b and 119 displayed moderate AChE inhibitory activities with 25-50% relative potencies. Meanwhile, the relative potencies of compounds 110a, 110c, 110e, 110f, 110j, 110k, 114a, 114b, 114c and 115a were less than 25%.