Synthesis and biological evaluation of 1, 3-dihydroxyxanthone mannich base derivatives as anticholinesterase agents

Abstract

BackgroundAlzheimer’s disease (AD), a progressive and degenerative disorder, has become one of the severe problems among the aged population all over the world. To use cholinesterase inhibitor drugs has become the most predominant treatment strategy for AD.ResultsA series of novel 1, 3-dihydroxyxanthone Mannich bases derivatives (1a ~ 4e) were synthesized, structure elucidated and evaluated for anti-cholinesterase activity. The result showed that most of the target compounds exhibited moderate to good inhibitory activities with the IC50 values at micromole level concentration against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The preliminary structure-activity indicated that: (i) The alkoxy or alkenoxy substituents in the position 3 of xanthone have a positive influence on the inhibition potency; (ii) types of dialkylamine methyl in position 2 of xanthone affected cholinesterase activities and AChE/BuChE selectivity. Among them, 2-((diethylamino)methyl)-1-hydroxy-3-(3-methylbut-2-enyloxy)-9H-xanthen-9-one showed potent inhibitory activity against AChE with the IC50 value of 2.61 ± 0.13 μM and the best inhibitory activity against BuChE with the IC50 value of 0.51 ± 0.01 μM. The results of a mixed-type manner in enzyme kinetic experiment and molecular docking study for 2-((diethylamino)methyl)-1-hydroxy-3-(3-methylbut-2-enyloxy)-9H-xanthen-9-one demonstrated that the Mannich base derivatives were likely to bind to the active site (AS) and the peripheral anionic site (PAS) of cholinesterases.ConclusionsThis study suggested that 1, 3-dihydroxyxanthone Mannich base derivatives were potential dual inhibitors of both AChE and BuChE, which may be considered as a kind of novel drug candidates for treatment of AD.

Kinetics and molecular docking studies of cholinesterase inhibitors derived from water layer of Lycopodiella cernua (L.) Pic. Serm. (II)

“…Natural flavonoids such as genistein derivatives [32], indole alkaloids [33,34], prenylated xanthones [35], and triterpenoids [36] have been reported to inhibit ChE. In our experiments, the mixed-type inhibitory mechanisms of our isolated compounds (4, 8, 13, and 15) are similar to the enzyme inhibitors above [28,29]. This is shown by the fact that our compounds not only compete with the substrate in the active site pocket, but can also bind to the enzyme-substrate complex.…”

“…Loss of cholinergic cells, particularly in the basal forebrain, is accompanied by loss of the neurotransmitter acetylcholine [25,26]. One approach is to inactivate AChE, the enzyme that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 13 one was identified as an AChE mixed-type inhibitor, and molecular docking studies suggested that it was most likely to bind to the active site and the peripheral anionic site of ChE [29]. Interestingly, although there have been a number of reports on the design and development of synthetic AChE inhibitors, several studies have discussed AChE inhibitors derived from plants [30,31].…”

Mannich bases in medicinal chemistry and drug design

“…Inhibitory activity against AChE and BuChE of phenolic Mannich bases 58 (R 1 ¼ H, CH 3 , allyl, prenyl; NR 2 ¼ N(CH 3 ) 2 , N(C 2 H 5 ) 2 , 1pyrrolidinyl, 1-piperidinyl, 4-morpholinyl) of xanthone derivatives ( Fig. 10) was found to be moderate to good compared to that of reference drug galantamine [467]. Candidates 58 derived from diethylamine as amine reagent in the Mannich reaction were generally the most potent inhibitors of both enzymes.…”

Shoot cultures of Hoppea fastigiata (Griseb.) C.B. Clarke as potential source of neuroprotective xanthones

“…For compound 2, the K m value of the enzyme with and without inhibitor remained the same (100 lM) whereas the V max value decreased, which indicated a non-competitive inhibition of AChE. It has been observed that substitution of hydroxyl, methoxyl, allyloxy and prenylated oxyl at the C-3 position in the xanthone skeleton with a methoxyl group at the C-3 position was the most effective in inhibiting AChE [35]. This supported the inhibitory properties of both compounds 1 and 2 which possessed a methoxyl group at the C-3 position.…”