Table 1.

Role of different hybrid compounds against AD

Hybrid compound	AChE inhibitor	β-amyloid antiaggregation	Antioxidant	Other activities	IC50 value(for AChE)	Clinical study	References
N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine (Cpd1A)	✔□			BChE inhibitory activities	51.3 nM	In vitro	[50]
6-Chloro-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9- amine (Cpd1B)	✔□			BChE inhibitory activities	11.2 nM	In vitro	[50]
Mixture of silibinin hemisuccinate and 6- aminohexamethylene tacrine (N1 -(1,2,3,4-tetrahydroacridin-9- yl)hexane-1,6-diamine)Cpd2	✔□		✔□	BChE inhibitory activities	53.9 nM	In vivo, In vitro	[51]
Oxoisoaporphine-tacrine	✔□	✔□		NA	nM range (41–57 nM)	In vitro	[52]
Tacrine–benzofuran hybrid Cpd 3	✔□	✔□	✔□	Metal chelation activity	38.6 nM	In vitro	[54]
Tacrine-melatonin hybrid	✔□		✔□	Able to cross BBB	0.008 nM(40 000-fold more potent than tacrine)	In vitro	[56]
Tacrine-ferulic acid hybrid	✔□	✔□	✔□	Inhibition of the PAS of AChE BChE inhibitory activities	4.4 nM	In vitro	[55]
Donepezil and Ebselen hybrid Cpd 4	✔□	✔□	✔□	Butyrylcholinesterase inhibitor (IC50 = 1.586 μM), peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min–1)	0.097 μM	In vitro	[44]
DNP based L-glutamic acid hybrid	✔□	✔□	✔□	BChE inhibitory activities, BBB permeation ability	0.10–0.53 μM	In vitro	[59]
N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3)	✔□			Protected rat hippocampal slices against oxygen–glucose deprivation, becoming promising anti-Alzheimer's and anti-stroke lead compounds	4.99 µM	In vitro	[60]
N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-1)	✔□			Blocks the voltage-dependent calcium channels	0.53 µM	In vitro	[60]
Donepezil-N(1benzylpiperidin4yl)5 aryl isoxazole 3 carboxamide derivative	✔□	✔□		BChE inhibitory activities	16.07 μM	In vitro	[61]
Donepezil-tacrine hybrid	✔□	✔□		BChE inhibition	Subnanomolar or low nanomolar range	In vitro and in silico	[63]
Donepezil-Benzylpiperidine hybrid	✔□	✔□	✔□	Tau hyperphosphorylation inhibition, metal chelation activity	4.0–30.0 μM	In silico	[62]
Carbamate derivative Cpd 6	✔□	✔□	✔□	Penetrates BBB, offers benign safety, neuroprotection, and pseudo-irreversible BChE inhibition	5.3 nM (for BChE)	In vivo and in silico	[65]
Indanone–carbamate hybrid Cpd 7	✔□	✔□		NA	4.64 μM	In vitro and in silico	[66]
Coumarin-dithiocarbamate hybrid Cpd 8	✔□	✔□		Metal-chelating ability, good BBB permeability and low toxicity on SH-SY5Y neuroblastoma cell	0.027 μM	In vitro and in vivo	[67]
Chromanone-dithiocarbamate hybrid Cpd 9	✔□	✔□		Ability to penetrate the BBB and low neurotoxicity in SH-SY5Y cells	0.10 μM	In vitro, in vivo and in silico	[68]
Phthalimide-dithiocarbamate hybrid Cpd 10	✔□			Anti BChE activity, possesses drug-like properties and able to cross the BBB	4.6 μM	In vitro and in silico	[69]
4′-aminochalcone-revastigmine hybrid	✔□	✔□	✔□	Selective monoamine oxidase B inhibitor and a selective biometal chelator	4.91 μM	In vitro	[72]
Scutellarein carbamate derivative Cpd 13	✔□		✔□	Bio-metal chelating and neuroprotective properties	0.57 μM	In vitro	[73]
4′-aminochalcone-revastigmine hybrid Cpd 12	✔□	✔□	✔□	Selective monoamine oxidase B inhibitor (IC50 = 0.29 μM) and a selective biometal chelator	4.91 μM	In vitro	[72]
2-methoxy-phenyl dimethyl-carbamate derivative Cpd 14B	✔□	✔□		Potent ABTS.+ scavenging and moderate copper ion chelating activity	0.097 μM	In vitro	[74]
Apigenin-rivastigmine hybrid Cpd 15	✔□	✔□	✔□	Remarkable dyskinesia recovery rate and response efficiency	6.8 μM	In vitro and in vivo	[76]
Phenserine	✔□	✔□		NA	22 nM	In vitro and in vivo	[80]
Tolserine	✔□			NA	0.01 µM	In vivo	[82]
Galantamine (GAL) and curcumin (CU) hybrid	✔□		✔□	NA	7.91 to 52.53 µM	In vitro	[88, 89][87]
Galantamine-camphane hybrid	✔□	✔□		NA	0.0029–0.0099 µM	In silico	[90]
Cpd 16	✔□	✔□		Tau hyperphosphorylation inhibition	2.39 nM	In vivo	[91]
Naphthyridine- and thienopyridine-based rhein-huprine hybrids	✔□	✔□	✔□	Tau hyperphosphorylation inhibition	3.60 nM	In vitro	[92]