Acid Hybrids Research Articles

Chemical Information and Computational Modeling of Targeting Hybrid Nucleic Acid Structures of PIM1 Sequences by Synthetic Pyrrole-Imidazole Carboxamide Drugs.

DNA can adopt various distinct structural motifs, such as quadruplex, duplex, i-motifs, etc. which have multifarious applications in biomedical therapeutics. Quadruplex-duplex hybrids (QDHs) consist of the juxtaposed quadruplex and duplex motifs and are thermally stable and biologically relevant. Selective binding toward these secondary structures plays an important role in the evaluation of the structure-specific ligands. Herein, several small molecules containing anthraquinone conjugated oligopyrrole, oligoimidazole, and pyrrole-imidazole derivatives have been screened for the binding of the quadruplex-duplex nucleic acid hybrids formed in PIM1 sequences through docking and molecular dynamics (MD) simulation studies. The binding interaction of the anthraquinone polypyrrole ligands has also been checked by performing different biophysical experiments. PIM1, being a coactivator of the MYC oncogene, can be targeted by these small molecules to control MYC expression which is overexpressed in the majority of human cancer cells. Accordingly, these cancer cell-specific and blood-compatible anthraquinone conjugated oligopyrrole ligands can be employed for anticancer therapeutic applications. Thus, the structure-activity relationship (SAR) of the screened ligands manifested prudent structural information for designing PIM1 QDHs targeting small molecules.

PH-sensitive carbon nanotubes graft polymethylacrylic acid self-assembly nanoplatforms for cellular drug release.

pH-Sensitive carbon nanotubes graft polymethylacrylic acid hybrids (CNTs-g-PMAA) were prepared through a three-step process, and self-assembled into core-shell micelle nanoparticles. The chemical structure of the hybrids were characterized by FTIR, 1H NMR and TGA. The critical micelle concentration (CMC) was measured by surface tension, and the value hinged on the Mn values or chain lengths of PMAA segments. The UV-vis transmittance, dynamical light scattering (DLS), and zeta potential measurements indicated that the hybrid self-assembly exhibited pH-sensentive responsiveness. The self-assembly was used to load an anticancer drug, paclitaxel (PTX), with an encapsulation efficiency of 77%. The PTX-loaded hybrid drug preparations were applied for cancer-cellular drug release, finding that the release rate was dependent on pH environments, and faster in acidic media of pH < 6.8 than in pH 7.4. MTT and hemolysis assays manifested that the blank hybrid drug carriers were nontoxic and safe, whereas the PTX-loaded drug preparations possessed comparable and even higher anticancer activity in comparison with free PTX. Consequently, the developed hybrid drug nanocarriers can be used for cancer therapy as a promising candidate.

Discovery of novel chloropyramine-cinnamic acid hybrids as potential FAK inhibitors for intervention of metastatic triple-negative breast cancer

To search for novel focal adhesion kinase (FAK) inhibitors for intervention of metastatic triple-negative breast cancer (TNBC), a series of hybrids 7a-s from chloropyramine and cinnamic acid analogs were designed, synthesized and biologically evaluated. The most active compound 7d could potently inhibit the proliferation, invasion and migration of TNBC cells in vitro. The docking analysis of 7d was performed to elucidate its possible binding modes to focal adhesion targeting (FAT) domain of FAK scaffold. Further mechanism studies indicated the ability of 7d in disrupting Y925 autophosphorylation of FAK, reducing formation of focal adhesions (FAs) and stress fibers (SFs) as well as inducing apoptosis of TNBC cells. Together, 7d is a novel FAK inhibitor to inhibit the essential nonkinase scaffolding function of FAK via binding FAT domain and may be worth studying further for intervention of TNBC.

Efficient capture of U(VI) by magnetic Zr(IV)-ethylenediamine tetramethylene phosphonic acid inorganic-organic hybrid.

The separation of magnetic adsorbents from aqueous solutions is made simple by using an external magnetic field. Herein, magnetic Zr(IV)-ethylenediamine tetramethylene phosphonic acid (EDTMPA) hybrids (MZrOP-x-T, x, and T were the different quality of Fe3O4@C and temperature in the synthesis process, respectively). A study was conducted on the uses of MZrOP-x-T in the capture of U(VI). The influences of pH, adsorption period, initial concentration, and temperature were all investigated. Furthermore, the desorption and reusability of the materials were explored. The optimal values of x and T were 0.2 g and 100 °C, respectively. At 298.15 K, the maximum adsorption capacity of MZrOP-0.2-100 was 330.30 mg·g-1. The current research demonstrates that MZrOP-0.2-100 is a potentially effective material in removing U(VI) from radioactive solution.

Cinnamic acid hybrids as anticancer agents: A mini-review.

Cancer, as a long-lasting and dramatic disease, affects almost one-third of human beings globally. Chemotherapeutics play an important role in cancer treatment, but multidrug resistance and severe adverse effects have already become the main causes of failure in tumor chemotherapy. Therefore, it is an urgent need to develop novel chemotherapeutics. Cinnamic acid contains a ubiquitous α,β-unsaturated acid moiety presenting potential therapeutic effects in the treatment of cancer asthese derivatives could act on cancer cells by diverse mechanisms of action. Accordingly, cinnamic acid derivatives are critical scaffolds in discovering novel anticancer agents. This review provides a comprehensive overview of cinnamic acid hybrids as anticancer agents. The structure-activity relationship, as well as the mechanisms of action, are also discussed, covering articles published from 2012 to 2021.

Phytic acid doped polyaniline-coupled g-C3N4 nanosheets for synergizing with APP promoting fire safety and waterproof performance of epoxy composites

In this study, polyaniline-coupled graphitic carbon nitride (g-C3N4) doped with phytic acid (CP@PA) hybrids are prepared by an in-situ chemical oxidative method. The CP@PA and APP (Ammonium Polyphosphate) are added into epoxy resin (EP) for EP composites. The characteristic test results show that CP@PA can react with epoxy resin (EP) to promote the curing of EP. And CP@PA disperses in EP uniformly. The cone calorimetry test (CCT) results show that the pHRR, THR, and TSP of EP-8A4CP@PA (the EP sample with 8.0 wt% APP and 4.0 wt% CP@PA) reduce 85%, 76.8%, and 78.9%, respectively than EP-0 (pure EP), which are lower than any other samples. The results of the back temperature test show that EP-8A4CP@PA has better thermal insulation and flame-retardant properties than EP-12APP (the EP sample with 12.0 wt% APP). Moreover, CP@PA promotes the waterproof properties of EP with APP composites by synergizing with APP to form a labyrinth effect. After a comprehensive analysis, the fire protection mechanisms of EP-8A4CP@PA are proposed as follows. CP@PA promote EP charring and make more aromatic structure remain in the char. And CP@PA has a synergistic effect with APP to promote EP to form porous intumescent char layer with a higher graphitic degree, which protects the composites from the flame. As a result, the combination of CP@PA and APP in EP achieved a lower addition of flame retardant and better waterproof and fire safety performance, which provides a specific experimental and theoretical basis for the further application of CP@PA in epoxy resin.

Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157-Lipoic Acid Hybrids for the Treatment of Alzheimer's Disease.

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.

Galleria mellonella: The Versatile Host for Drug Discovery, In Vivo Toxicity Testing and Characterising Host-Pathogen Interactions.

Larvae of the greater wax moth, Galleria mellonella, are a convenient in vivo model for assessing the activity and toxicity of antimicrobial agents and for studying the immune response to pathogens and provide results similar to those from mammals. G. mellonella larvae are now widely used in academia and industry and their use can assist in the identification and evaluation of novel antimicrobial agents. Galleria larvae are inexpensive to purchase and house, easy to inoculate, generate results within 24–48 h and their use is not restricted by legal or ethical considerations. This review will highlight how Galleria larvae can be used to assess the efficacy of novel antimicrobial therapies (photodynamic therapy, phage therapy, metal-based drugs, triazole-amino acid hybrids) and for determining the in vivo toxicity of compounds (e.g., food preservatives, ionic liquids) and/or solvents (polysorbate 80). In addition, the disease development processes are associated with a variety of pathogens (e.g., Staphylococcus aureus, Listeria monocytogenes, Aspergillus fumigatus, Madurella mycotomatis) in mammals are also present in Galleria larvae thus providing a simple in vivo model for characterising disease progression. The use of Galleria larvae offers many advantages and can lead to an acceleration in the development of novel antimicrobials and may be a prerequisite to mammalian testing.

Amino Acid-Viologen Hybrids: Synthesis, Cucurbituril Host-Guest Chemistry, and Implementation on the Production of Peptides.

We present herein the development of a series of viologen–amino acid hybrids, obtained in good yields either by successive alkylations of 4,4′-bipyridine, or by Zincke reactions followed by a second alkylation step. The potential of the obtained amino acids has been exemplified, either as typical guests of the curcubituril family of hosts (particularly CB[7]/[8]) or as suitable building blocks for the solution/solid-phase synthesis of two model tripeptides with the viologen core inserted within their sequences.

Heterologous Expression of Macrollins from Phytopathogenic Macrophomina phaseolina Revealed a Cytochrome P450 Mono-oxygenase in the Biosynthesis of β-Hydroxyl Tetramic Acid.

Macrophomina phaseolina (M. phaseolina) is a crucial pathogenic fungus that can cause severe charcoal rot in economic crops and other plants. In this study, four new natural products, macrollins A-D, were discovered from M. phaseolina by the strategy of heterologous expression. To our knowledge, macrollins are the first reported polyketide-amino acid hybrids from the plant pathogen. Heterologous expression and in vitro reactions revealed a cytochrome P450 mono-oxygenase (MacC) catalyzing the hydroxylation at the β-carbon of tetramic acid molecules, which is different from P450s leading to the ring expansion in the biosynthesis of fungal 2-pyridones. Phylogenetic analysis of P450s involved in the fungal polyketide-amino acid hybrids showed that MacC was not classified in any known clades. The putative oxidative mechanisms of the P450s and the biosynthetic pathway of macrollins were also proposed.

Biological Evaluation of 4-(1H-triazol-1-yl)benzoic Acid Hybrids as Antioxidant Agents: In Vitro Screening and DFT Study

Fourteen triazole benzoic acid hybrids were previously characterized. This work aimed to screen their in vitro antioxidant activity using different assays, i.e., DPPH (1,1-diphenyl-1-picrylhydrazyl), reducing the power capability, FRAP (ferric reducing antioxidants power) and ABTS (2,2′-azino-bis(3-ethylben zothiazoline-6-sulfonate) radical scavenging. The 14 compounds showed antioxidant properties in relation to standard BHA (butylated hydroxylanisole) and Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Higher antioxidant activity was observed by the parent (1) at a concentration of 100 µg/mL (89.95 ± 0.34 and 88.59 ± 0.13%) when tested by DPPH and ABTS methods in relation to BHA at 100 µg/mL (95.02 ± 0.74 and 96.18 ± 0.33%). The parent (2) demonstrated remarkable scavenging activity when tested by ABTS (62.00 ± 0.24%), however, 3 was less active (29.98 ± 0.13%). Compounds 5, 6, 9, and 11 exhibited good scavenging activity compared to 1. DFT studies were performed using the B3LYP/6-311++g (2d,2p) level of theory to evaluate different antioxidant descriptors for the targets. Three antioxidant mechanisms, i.e., hydrogen atom transfer (HAT), sequential electron transfer proton transfer (SETPT) and sequential proton loss electron transfer (SPLET) were suggested to describe the antioxidant properties of 1–14. Out of the 14 triazole benzoic acid hybrids, 5, 9, 6, and 11 showed some good theoretical results, which were in agreement with some experimental outcomes. Based on the computed (PA and ETE) and (BDE and IP) values in (SPLET) and (HAT and SETPT) mechanisms, respectively, compound 9 emerged has having good antioxidant activity.

8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules.

Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range; no significant dissociation occurs at physiological pH. The hybrids and their Rh(η5-C5Me5) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η5-C5Me5) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells; meanwhile, the Ru(η6-p-cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η5-C5Me5) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding.

Novel C3N4/PANI@PA for enhancement of fire protection and smoke suppression in intumescent fire retardant epoxy coatings

Graphitic carbon nitride/polyaniline doped with phosphoric acid (g-C3N4/PANI@PA) hybrids was prepared by polymerising aniline monomer on the surface of g-C3N4 nanosheets, which used an in-situ chemical oxidative polymerisation method. Intumescent fire retardant (IFR) epoxy coatings with g-C3N4/PANI@PA were prepared, and fire resistance and waterproofing performance of coatings were investigated. The energy dispersive X-ray spectrometry image showed phosphorus element dispersing evenly on the fracture surface of epoxy composite with 0.25 wt% g-C3N4/PANI@PA (EP-0.25CP@PA), which indicated that g-C3N4/PANI@PA dispersed in coating evenly. The results of the cone calorimeter test (CCT) showed that the values of peak heat release rate (pHRR), total smoke release (TSR), total carbon monoxide production (TCOP) of pure epoxy resin (EP-0) were 1389.0 kW/m2, 22.6 m2 and 3.6 g, respectively. In addition, the related data of intumescent fire retardant coating (EP-IFR) were 374.8 kW/m2, 12.9 m2, and 2.1 g, respectively. When 0.25 wt% g-C3N4/PANI@PA was introduced into EP-IFR to get EP-IFR-0.25CP@PA sample, the pHRR, TSR, and TCOP values were reduced to 347.3 kW/m2, 7.9 m2, 1.5 g, which were reduced by 75.0%, 65.0%, and 60.0% compared with EP-0, respectively. Furthermore, g-C3N4/PANI@PA could also improve the hydrophobicity of IFR epoxy coatings. The water contact angle increased from 50.0° (EP-IFR) to 84.8° (EP-IFR-0.25CP@PA). It was confirmed that g-C3N4/PANI@PA could improve the fire protection, smoke suppression performance, and waterproof performance of IFR epoxy coating. All of those provide a certain theoretical support for applying g-C3N4/PANI@PA in intumescent fire retardant coatings.

Synthesis of water-soluble ester-linked ursolic acid–gallic acid hybrids with various hydrolytic stabilities

To obtain derivatives of ursolic acid with improved water solubility and antioxidant activity, new ester-linked hybrids of ursolic acid and gallic acid were synthesized. In the reaction of methyl gallate with ursoloyl chloride acetate, both mono- and diacylation products were obtained. To prepare mono-alkylated and mono-acylated derivatives of gallic acid, 4,5-O-methoxymethylene-protected methyl gallate was used. It was found that ursolic-gallic acid hybrids containing phenolic ester linkage readily underwent hydrolysis at C-28 of triterpenoid. The dioxolane protection allowed selective hydrolysis of the methyl ester at the aromatic moiety of the hybrid compound leaving intact the labile C-28 ester at the triterpenoid moiety. The hybrids possessing an ester–ether linker (terpenoid-COO–CH2CH2–O-aryl) are stable to the hydrolysis. The majority of the obtained ursolic–gallic acid hybrids containing free phenolic hydroxyl groups possess excellent antioxidant activity. Notable water solubilities (∼0.5 mg/mL) of novel hybrids containing both carboxyl group and hydroxyls at aromatic moiety were found.

Two new 5/6/6 polyketide-amino acid hybrids from a genetic mutant of Periconia sp. F-31

Peridecalins C and D (1 and 2), one decalin and one oxygen-decalin containing polyketide-amino acid hybrids with 5/6/6 ring system, was isolated from a genetic mutant of Periconia sp. F-31. Their structures were elucidated through extensive spectroscopic data analysis, including 1 D/2D NMR and HR-MS spectra. Biosynthetically, two proposed Diels-Alder reactions are supposed to be involved in the skeleton construction of 1 and 2.

Synthesis of New Lansiumamide A/Alatamide (cis‐Isomer) Based Unnatural α‐Amino Acid Derivatives via the Suzuki‐Miyaura Cross Coupling as Key Step

AbstractWe have developed a new synthetic method for the preparation of Lansiumamide‐amino acid (1) as well as Alatamide (cis‐isomer)‐amino acid (2) hybrids. The key step involves the Suzuki coupling reaction of N‐((Z)‐2‐bromovinyl) cinnamamide with phenylboronic acid and (Z)‐N‐(2‐iodovinyl)benzamide with 4‐methoxy phenylboronic acid. The Suzuki coupling of N‐((E)‐2‐bromo‐2‐phenylvinyl) cinnamamide as well as (E)‐N‐(2‐Iodo‐2‐(4‐methoxyphenyl)vinyl)benzamide with 4‐borono‐pinacol ester of phenylalanine to give the Lansiumamide‐phenylalanine and Alatamide (cis‐isomer)‐phenylalanine amino acid hybrids in good yields. This is the first synthesis of C‐linked Lansiumamide A and Alatamide (cis‐isomer)‐amino acid conjugates where both the natural products are linked to amino acid through C−C bond.

Discovery of Novel Dihydropyrimidine and hydroxamic acid hybrids as potent Helicobacter pylori Urease inhibitors

Two novel series of Dihydropyrimidine-hydroxamic acid hybrids (4a-4l and 5a-5l) were designed, synthesized and evaluated for in vitro Helicobacter pylori urease inhibition. In vitro enzyme inhibition screening led to the discovery of three potent urease inhibitors 2-[[4-(4-hydroxy phenyl)-6-oxo-1,6-dihydropyrimidine-2-yl]-amino]-N-hydroxy acetamide (4g), 2-[[4-(4-chloro phenyl)-6-oxo-1,6-dihydropyrimidine-2-yl]-amino]-N-hydroxy acetamide (4b) and 3-[[4-(3-methoxy phenyl)-6-oxo-1,6-dihydropyrimidine-2-yl]-amino]-N-hydroxy propanamide (5l). Compound 4g showed excellent urease inhibition with IC50 value of 14 ± 1 nM, indicated by its strong interactions with both metallic Ni++ ions, Gly279, His221, Ala365, Asp362, Asn168, Arg338 and His322 residues of the active site of urease. Further, compounds 4b and 5l displayed very good activity with IC50 value of 0.082 ± 0.004 µM and 0.14 ± 0.013 µM respectively compared to standard Acetohydroxamic acid (IC50 – 27.4 ± 1.2 µM). Kinetic studies revealed that a mixed inhibition with both competitive and non-competitive aspects is involved in the urease inhibition mechanism. The in vitro urease inhibition results were supported by molecular docking studies. Collectively, this study indicates that 4g could be considered as promising lead molecule that can be further developed as a potent drug molecule for the treatment of Helicobacter pylori caused gastritis for further studies.

An efficient approach to diarylethene-amino acid photochromic fluorescent hybrids

• An effective approach to creating photo-controlled diarylethene-amino acid hybrids. • X-ray diffraction study, spectral luminescent and photochromic properties. • Thermally and photochemically reversible intramolecular photocyclization. • Dependence of the photoinduced form stability on the structure. • Modulation of emission under successive irradiation with light of different wavelengths. An effective approach to the synthesis of diarylethene-amino acid hybrids DE-Gly, DE-AABA and DE-DAA ( 5a-d - 7-a-d ) was developed via condensation of furan-2,5-dione-based diarylethenes (DE) and ethyl esters of glycine (Gly), α-aminobutyric acid (AABA) and D-aspartic acid (DAA) with moderate to good yields. According to X-ray diffraction data, DE-Gly hybrid 5a exists in an antiparallel conformation with a distance of 4.549 Å between the reactive carbon atoms C(1)-C(11), potentially capable of forming a single bond, which is suitable for the conrotatory photocyclization reaction allowed by the Woodward-Hoffman rules. The structures of the obtained compounds were proved by 1 H, COZY, HSQC, HMBC and 13 C NMR spectroscopy. The hybrids DE-Gly, DE-AABA and DE-DAA absorb at 443–456 nm, which corresponds to their existence in a ring-open form O, and display fluorescence at 531–612 nm. Irradiation with light of 436 nm results in their rearrangement into ring-closed colored nonfluorescent isomers C. Backwards re-opening occurs under the action of visible light (λ > 500 nm). Spectral kinetic investigation of 5a,c revealed that the efficiency of photocyclization, as well as the emission quantum yield, decreases with the growth of solvent polarity. The ring-closed isomer C of sterically hindered 5a (R 2 = R 3 = Me) is stable at room temperature, whereas for 5c (R 3 = H), ring opening readily occurs with the speed increasing with the polarity of the solvent. The internal emission of sterically hindered hybrids 5a, 6a and 7a (R 2 = R 3 = Me) is reversibly modulated in a binary response with good fatigue resistance under successive irradiation with light of 436 and 540 nm.

Discovery of novel dihydroartemisinin-cinnamic hybrids inducing lung cancer cells apoptosis via inhibition of Akt/Bad signal pathway

A series of dihydroartemisinin-cinnamic acid hybrids were designed, synthesized and evaluated. Most of the tested compounds showed enhanced anti-proliferative activities than artemisinin and dihydroartemisinin, among which 16 g had the superior potency with IC50 values ranging from 5.07 μM to 7.88 μM against four tested cancer cell lines. The cell cycle arrest revealed that 16 g induced A549 cell cycle arrest at G0/G1 phase via regulation of G1-related protein expression (Cdk4). Further mechanism studies reveal that 16 g induced A549 cells apoptosis via inhibiting Akt/Bad pathway. Moreover, 16 g depolarized the mitochondria membrane potentials and induced ROS generation in A549. Additionally, 16 g blocked migration of A549 cells in a concentration-dependent manner. What’s more, 16 g is barely nontoxic to zebrafish embryos. Overall, the cell cycle arrest, inhibition of Akt/Bad signal pathway, ROS generation and migration blocked might explain the potent anti-proliferative activities of these compounds.

Design, synthesis and evaluation of cinnamic acid hybrids as multi-target-directed agents for the treatment of Alzheimer’s disease

Herein, combining 1,2,3,4-tetrahydroisoquinoline and benzylpiperidine groups into cinnamic acid derivatives, a series of novel cinnamic acid hybrids was rationally designed, synthesized and evaluated by the multi-target-directed ligands (MTDLs) strategy. Hybrid 4e was the most promising one among these hybrids with a reversible huBuChE inhibitor (IC50 = 2.5 μM) and good MAO-B inhibition activity (IC50 = 1.3 μM) and antioxidant potency (ORAC = 0.4 eq). Moreover, compound 4e significantly inhibited self-mediated Aβ1-42 aggregation (65.2% inhibition rate). Compound 4e exhibited remarkable anti-inflammatory propery and neuroprotective effect. Furthermore, compound 4e displayed favourable blood–brain barrier penetration via parallel artificial membrane permeation assay (PAMPA). The obtained results also revealed that compound 4e significantly improved dyskinesia recovery rate and response efficiency on AD model zebrafish. Further, 4e did not show obvious acute toxicity at dose up to 1500 mg/kg in vivo and improved scopolamine-induced memory impairment. Importantly, compound 4e showed good stability in both artificial gastric fluid and artificial intestinal fluid. Therefore, compound 4e presented a promising multi-targeted active molecule for treating AD.