Promising Multifunctional Agent Research Articles

Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease.

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC50 15.1 ± 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d: IC50 5.96 ± 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited the inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.

Design, synthesis, and biological evaluation of thienopyrimidine derivatives as multifunctional agents against Alzheimer's disease.

A series of 12 S-substituted tetrahydrobenzothienopyrimidines were designed and synthesized based on the donepezil scaffold. All the newly synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and the most active compounds were tested for their butyrylcholinesterase (BuChE) inhibitory activity. Moreover, all the synthesized compounds were evaluated for their inhibitory effects against Aβ aggregation and antioxidant activity using the oxygen radical absorbance capacity method. Compounds 4b, 6b, and 8b displayed the most prominent AChE inhibitory action comparable to donepezil. Compound 6b showed the greatest AChE inhibitory action (IC50 = 0.07 ± 0.003 µM) and the most potent BuChE inhibitory action (IC50 = 0.059 ± 0.004 µM). Furthermore, the three compounds exhibited significant antioxidant activity. Compounds 6b and 8b exerted more inhibitory action on Aβ aggregation than donepezil. The cytotoxic activity of compounds 4b, 6b, and 8b against the WI-38 cell line in comparison with donepezil was examined using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. The results revealed that compounds 6b and 8b were less cytotixic than donepezil, while compound 4b showed nonsignificant cytotoxicity compared to donepezil. For more insights about the binding patterns of the most promising compounds (4b, 6b, and 8b) with the AChE at molecular levels; molecular docking and molecular dynamics simulations were performed. The densityfunctional theory calculations and absorption, distribution, metabolism, excretion and toxicity properties were described as well. The results highlighted compound 6b, which incorporates a phenylpiperazine moiety coupled to a thienopyrimidone scaffold via two-atom spacer, to be a promising multifunctional therapeutic agent for the treatment of Alzheimer's disease. It is a potent dual AChE and BuChE inhibitor. Furthermore, it had stronger Aβ aggregation inhibitory action than donepezil. Additionally, compound 6b exerted significant antioxidant activity.

Delivery of miR-3529-3p using MnO2 -SiO2 -APTES nanoparticles combined with phototherapy suppresses lung adenocarcinoma progression by targeting HIGD1A.

The present study aimed to investigate the function of miR-3529-3p in lung adenocarcinoma and MnO2 -SiO2 -APTES (MSA) as a promising multifunctional delivery agent for lung adenocarcinoma therapy. Expression levels of miR-3529-3p were evaluated in lung carcinoma cells and tissues by qRT-PCR. The effects of miR-3529-3p on apoptosis, proliferation, metastasis and neovascularization were assessed by CCK-8, FACS, transwell and wound healing assays, tube formation and xenografts experiments. Luciferase reporter assays, western blot, qRT-PCR and mitochondrial complex assay were used to determine the targeting relationship between miR-3529-3p and hypoxia-inducible gene domain family member 1A (HIGD1A). MSA was fabricated using MnO2 nanoflowers, and its heating curves, temperature curves, IC50, and delivery efficiency were examined. The hypoxia and reactive oxygen species (ROS) production was investigated by nitro reductase probing, DCFH-DA staining and FACS. MiR-3529-3p expression was reduced in lung carcinoma tissues and cells. Transfection of miR-3529-3p could promote apoptosis and suppress cell proliferation, migration and angiogenesis. As a target of miR-3529-3p, HIGD1A expression was downregulated, through which miR-3529-3p could disrupt the activities of complexes III and IV of the respiratory chain. The multifunctional nanoparticle MSA could not only efficiently deliver miR-3529-3p into cells, but also enhance the antitumor function of miR-3529-3p. The underlying mechanism may be that MSA alleviates hypoxia and has synergistic effects in cellular ROS promotion with miR-3529-3p. Our results establish the antioncogenic role of miR-3529-3p, and demonstrate that miR-3529-3p delivered by MSA has enhanced tumor suppressive effects, probably through elevating ROS production and thermogenesis.

Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer's Disease.

A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. ABTS•+-scavenging activity was highest for salicylamides 5a-c, intermediate for salicylimines 10a-c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure-activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.

Design, synthesis and evaluation of quinoline-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer’s disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual eeAChE/eqBuChE inhibitor with IC50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1β and NO. In addition, compound 3f presented significant neuroprotective effect on Aβ 25-35-induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl3-induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.

N-Substituted piperidine-3-carbohydrazide-hydrazones against Alzheimer's disease: Synthesis and evaluation of cholinesterase, beta-amyloid inhibitory activity, and antioxidant capacity.

A series of piperidine-3-carbohydrazide-hydrazones bearing phenylethyl, phenylpropyl, and phenylbutyl substituents on piperidine nitrogen were designed and synthesized as cholinesterase (ChE) inhibitors. The title compounds were screened for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory activitiesand antioxidant capacities, and the active ones for Aβ42 self-aggregation inhibition, in vitro. The chemiluminescence method was used to determine the effect of the selected compounds on the reactive oxygen species (ROS) levels in brain tissue. Physicochemical properties were calculated by theMOE program. Kinetic analysis and molecular modeling studies were also carried out for the most active compounds. Generally, the final compounds exhibited moderate to good AChE or BuChE inhibitory activity. Among them, 3g and 3j showed the most potent activity against AChE (IC50 = 4.32 µM) and BuChE (IC50 = 1.27 µM), respectively. The kinetic results showed that both compounds exhibited mixed-type inhibition. Among the selected compounds, nitro derivatives (3g, 4g, and5g) provided better Aβ42 inhibition. According to the chemiluminescence assay, 4i exhibited the most active superoxide free-radical scavenger activity and 3g, 3j, and 4i showed similar scavenger activity on other ROS. All results suggested that 3g, 3j, and 4i have good AChE/BuChE, Aβ42 inhibitory potentials and antioxidant capacities and can therefore be suggested as promising multifunctional agents to combat Alzheimer's disease.

All-in-one phototheranostics based on BTP-4F-DMO nanoparticles for NIR-II fluorescence/photoacoustic dual-mode imaging and combinational therapy

Various phototheranostics have recently been developed for phototherapy. Through proper molecular design, the photochemical and photophysical properties of these phototheranostics can be promoted. Herein, an acceptor-donor-acceptor (A-D-A)-structured dye, BTP-4F-DMO, was synthesized and prepared into water-soluble nanoparticles (NPs). The obtained BTP-4F-DMO NPs had strong absorption from 650 nm to 850 nm and a fluorescence emission peak at ∼900 nm that tailed to ∼1100 nm. The NPs showed a superhigh photothermal conversion efficiency of 90.5% ± 5% and could simultaneously generate •OH and 1O2 with a 1O2 generation quantum yield of 4.6% under 808 nm laser irradiation. Due to these advanced properties, BTP-4F-DMO NPs can switch the role of autophagy from pro-survival to pro-death, thereby further promoting cancer cell death. These features make BTP-4F-DMO NPs a promising multifunctional phototheranostic agent for NIR-II fluorescence/photoacoustic dual-mode imaging-guided synergetic photodynamic/photothermal therapy. In general, this work provides a strategy for expanding the biomedical applications of organic A-D-A-structured phototheranostics.

AIE-Active Antibiotic Photosensitizer with Enhanced Fluorescence in Bacteria Infected Cells and Better Therapy Effect toward Drug-Resistant Bacteria.

It is well-known that bacterial infections will induce a variety of diseases in the clinic. In particular, the emergence of drug-resistant bacteria has increased the threat to human health. The development of multiple modes of therapy will effectively fight against drug-resistant bacterial infections. In this work, we covalently attached an AIE photosensitizer to the antibiotic of moxifloxacin hydrochloride (MXF-HCl) and synthesized an antibiotic derivative, MXF-R, with pharmacological activity and photodynamic activation. In infected cells, MXF-R showed enhanced fluorescence after it specifically binds to bacteria; thus, in situ visualization of the bacteria was realized. Notably, through chemo- and photodynamic therapy, MXF-R exhibited better antibacterial activity than its parent antibiotic in rapid sterilization, and it achieved effective killing for moxifloxacin resistant bacteria. In addition, MXF-R shows a broad-spectrum antibacterial effect and could be used in the recovery therapy of infected wounds in mice, demonstrative of a significant therapeutic effect and good biological safety. Thus, as a promising multifunctional antibacterial agent, MXF-R will have tremendous potential in in situ visualization study and killing of drug-resistant bacteria. This work provides an innovative strategy for solving critical disease through the combination of materials and biomedical sciences.

Rational surface modification of gadolinium borate nanoparticles enhancing colloidal stability in physiological media for potential neutron capture therapy and magnetic resonance imaging

Colloidal stability of nanomaterials in physiological media is an indispensable property for their biomedical applications. However, gadolinium borate (GdBO3) nanoparticles that hold promise as a theranostic agent for neutron capture therapy (NCT) and magnetic resonance imaging (MRI) of cancer tend to precipitate in phosphate buffered saline (PBS) owing to formation of insoluble gadolinium phosphate. To address this issue, in this work 10B-enriched GdBO3 nanoparticles were prepared and coated with mesoporous silica (mSiO2) of ~ 40 nm in thickness and subsequently grafted with hydrophilic polyglycerol (PG). The resulting GdBO3 @mSiO2-PG nanoparticles showed excellent colloidal stability in PBS due to the protection of the mSiO2 coating as well as superior dispersibility because of the high hydrophilicity of the PG layer. In vitro experiments revealed that GdBO3 @mSiO2-PG possessed low cytotoxicity and could be taken up by cancer cells in a concentration-dependent manner. In vivo studies indicated that GdBO3 @mSiO2-PG can circulate in mouse body for a considerably long time without obvious acute toxicity. In addition, GdBO3 @mSiO2-PG also showed promise as a T1-weighted MRI contrast agent with a proton longitudinal relaxivity of 0.67 mM−1 s−1. Our results indicate that GdBO3 @mSiO2-PG with enhanced colloidal stability in physiological media could serve as a promising multifunctional agent for cancer theranostics.

Design, synthesis, and biological evaluation of thienopyrimidine and thienotriazine derivatives as multitarget anti-Alzheimer agents.

A series of tetrahydrobenzothienopyrimidines and tetrahydrobenzothienotriazines incorporating a pharmacophore from donepezil molecule were designed and synthesized. The 12 newly synthesized compounds were screened for their inhibition activity against acetylcholinesterase enzyme (AChE). Compounds that exerted the most potent AChE inhibitory action were further evaluated for their BChE inhibitory activity. In addition, the inhibitory effects of all newly synthesized compounds on Aβ and reactive oxygen species were assessed. Compounds 4d, 10b, and 10c showed potent inhibitory activity on AChE comparable to donepezil. Compound 10b (IC50 = 0.124 ± 0.006 nM) showed the greatest AChE inhibitory action and the most potent BChE inhibitory action (IC50 = 0.379 ± 0.02 nM). These three compounds showed more inhibitory action on Aβ accumulation than donepezil. Moreover, they showed potent antioxidant activity. The binding pattern of compounds 4d and 10b into AChE active site rationalized their remarkable AChE inhibitory activity. Taken together, these results indicated that these derivatives could be promising multifunctional agents for Alzheimer's disease management.

Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer's disease

Recently, the discovery of multifunctional molecules that target different factors in the treatment of dementia is a significant research area. Both PDE4 and AChE inhibitors display improvement in cognitive and memory function. In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC50 = 0.28 μM) and PDE4D (IC50 = 1.88 μM). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed more potent anti-neuroinflammation than the donepezil and drug combination (donepezil + rolipram) groups. These results suggest that 12C is a promising multifunctional agent for the treatment of AD.

Laser-ablative aqueous synthesis and characterization of elemental boron nanoparticles for biomedical applications

Boron-based nano-formulations look very promising for biomedical applications, including photo- and boron neutron capture therapies, but the fabrication of non-toxic water-dispersible boron nanoparticles (NPs), which contain the highest boron atom concentration, is difficult using currently available chemical and plasma synthesis methods. Here, we demonstrate purely aqueous synthesis of clean boron NPs by methods of femtosecond laser ablation from a solid boron target in water, thus free of any toxic organic solvents, and characterize their properties. We show that despite highly oxidizing water ambience, the laser-ablative synthesis process follows an unusual scenario leading to the formation of boron NPs together with boric acid (H3BO3) as an oxidation by-product coating the nanoparticles, which acts to stabilize the elemental boron NPs dispersion. We then demonstrate the purification of boron NPs from residual boric acid in deionized water, followed by their coating with polyethylene glycol to improve colloidal stability and biocompatibility. It was found that the formed NPs have a spherical shape with averaged size of about 37 nm, and are composed of elemental boron in mostly amorphous phase with the presence of certain crystalline fraction. The synthesized NPs demonstrate low toxicity and exhibit strong absorption in the NIR window of relative tissue transparency, promising their use in photoacoustic imaging and phototherapy, in addition to their promise for neutron capture therapy. This combined potential ability of generating imaging and therapy functionalities makes laser-synthesized B NPs a very promising multifunctional agent for biomedical applications.

Design, synthesis, and biological evaluation of novel 2-acetylphenol-rivastigmine hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease

Herein, a series of 2-acetylphenol-rivastigmine hybrids were rationally designed as multifunctional agents for the treatment of AD through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c was a pseudo-irreversible and selective huAChE inhibitor (IC50 = 8.7 μM). Compound 3c was also a significant antioxidant with ORAC value of 1.2 eq. Moreover, compound 3c showed potent MAO-B inhibitory activity with IC50 values of 2.9 μM. In addition, compound 3c displayed selective metal chelation property. Furthermore, compound 3c showed significant neuroprotective effect on H2O2-induced PC12 cells injury. More importantly, compound 3c displayed favorable drug-like property and good blood brain barrier permeability in vitro. Thus, compound 3c was a promising multifunctional agent in vitro for the treatment of AD, deserving for further investigations. Graphical abstract

Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer’s disease

Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC50 = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Aβ 1-42 aggregation, and potent neuroprotective effect on Aβ 1-42-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood–brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [11C]5f demonstrated that [11C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.

Computational and pharmacokinetics studies of 1,3-dimethylbenzimidazolinone analogues of new proposed agent against Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a multifactorial disorder that gradually destroys wisdom and memory skills. Currently, this disease can only be treated palliatively. However, the molecular mechanisms underlying this condition remain elusive. Therefore, these treatments are inadequate. Current medications can only increase patient warning signs. Chemical structures were drawn using Chemsketch software. Spartan’14 software was used to optimize the structures using density functional theory (DFT). The PaDEL software was used to generate the descriptors. The genetic function algorithm (GFA) and multi-linear regression (MLR) approaches were used to generate the QSAR model.ResultsIn the present study, we performed a computational investigation, molecular docking, and pharmacokinetics analysis of 1,3-dimethylbenzimidazolinone derivatives. The descriptors generated in the model are AATS7i, MATS5p, SpMin7_Bhe, and GATS6c. Compounds 13 and 21 have the best binding scores, 11.2 kcal/mol and 10.8 kcal/mol, respectively, and optimal protein–ligand interactions with AChE. These compounds have brilliant pharmacokinetic and physicochemical properties.ConclusionsThe model was validated and found to have good internal and external assessment parameters: R2 = 0.937, R_{{{text{adj}}}}^{2} = 0.863, Q_{{{text{cv}}}}^{2} = 0.788, R_{{{text{test}}}}^{2} = 0.756, LOF = 0.0268, cR_{{text{p}}}^{2} = 0.677. In summary, these data suggested that compounds 13 and 21 are promising multifunctional agents against AD.

Development of naringenin-O-carbamate derivatives as multi-target-directed liagnds for the treatment of Alzheimer’s disease

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer’s disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC50 = 9.7 μM) inhibitor. In addition, compound 3c significantly inhibited self-induced Aβ1-42 aggregation, and it could activate UPS degradation pathway in HT22 cells and clear the aggregated proteins associated with AD. Moreover, compound 3c was a selective metal chelator, and it significantly inhibited and disaggregated Cu2+-mediated Aβ1-42 aggregation. Furthermore, compound 3c displayed remarkable neuroprotective effect and anti-inflammatory property. Interestingly, compound 3c displayed good hepatoprotective effect by its antioxidant activity. More importantly, compound 3c demonstrated favourable blood–brain barrier penetration in vitro and drug-like property. Therefore, compound 3c was a promising multifunctional agent for the treatment of AD.

Design, synthesis, and biological evaluation of carbamate derivatives of N-salicyloyl tryptamine as multifunctional agents for the treatment of Alzheimer's disease

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aβ1-42. Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation, pharmacokinetics, ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.

Development of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives as multifunctional agents for Alzheimer’s disease treatment

Due to the complex pathogenesis of AD, the multitarget-directed ligands (MTDLs) strategy presented the best pharmacological option for AD treatment. Herein, a series of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives (5a–f and 6a–f) was rationally designed and synthesized. Of these derivatives, 5c was a good multifunctional agent (eeAChE IC50 = 7.9 μM, MAO-B IC50 = 9.9 μM, BACE1 IC50 = 8.3 μM) in vitro and displayed a mixed-type AChE inhibition, which could bind to the CAS and PAS of AChE. Compound 5c also exhibited good antioxidant activity (ORAC = 2.5 eq) and neuroprotective effects. Furthermore, compound 5c was a selective metal ions chelator. And it could cross blood–brain barrier in vitro and complied with drug-like properties rule of 5. Therefore, compound 5c was a promising multifunctional agent for the treatment of AD.

Design, synthesis and evaluation of novel dimethylamino chalcone-O-alkylamines derivatives as potential multifunctional agents against Alzheimer's disease.

A novel series of dimethylamino chalcone-O-alkylamines derivatives was designed and synthesized as multifunctional agents for the treatment of AD. All the target compounds exhibited significant abilities to inhibit and disaggregate Aβ aggregation, and acted as potential selective AChE inhibitors, biometal chelators and selective MAO-B inhibitors. Among these compounds, compound TM-6 showed the greatest inhibitory activity against self-induced Aβ aggregation (IC50=0.88μM) and well disaggregation ability toward self-induced Aβ aggregation (95.1%, 25μM), the TEM images, molecular docking study and molecular dynamics simulations provided reasonable explanation for its high efficiency, and it was also found to be a remarkable antioxidant (ORAC-FL values of 2.1eq.), the best AChE inhibitor (IC50=0.13μM) and MAO-B inhibitor (IC50=1.0μM), as well as a good neuroprotectant. UV-visual spectrometry and ThT fluorescence assay revealed that compound TM-6 was not only a good biometal chelator by inhibiting Cu2+-induced Aβ aggregation (95.3%, 25μM) but also could disassemble the well-structured Aβ fibrils (88.1%, 25μM). Further, TM-6 could cross the blood-brain barrier (BBB) invitro. More importantly, compound TM-6 did not show any acute toxicity in mice at doses of up to 1000mg/kg and improved scopolamine-induced memory impairment. Taken together, these data indicated that TM-6, an excellent balanced multifunctional inhibitor, was a potential lead compound for the treatment of AD.

Eco-Friendly Preparation of Epoxy-Rich Graphene Oxide for Wound Healing.

Despite the ever-growing endangerment caused by the multidrug resistance (MDR) of bacteria, the development of effective antibacterial materials still remains a global challenge. Current antibiotic therapies cannot simultaneously inactivate bacteria and accelerate wound healing. This study aimed to originally separate the intercalation of MnO3+ and the oxidation processes to synthesize epoxy-rich graphene oxide (erGO) nanofilms via an eco-friendly synthetic route, which possessed low density and large lamellar distribution and was rich in epoxide. Importantly, the MnO3+ could be separated from the product and recycled for preparing the next generation of erGO nanofilms, which was quite economical and eco-friendly. The erGO nanofilm was capable of successfully inhibiting Gram-negative bacteria and even had excellent growth-inhibitory effects on Gram-positive bacteria including multidrug resistance (MDR) bacteria, as evidenced by antibacterial phenomena. Additionally, the erGO nanofilm with high •C density formed from epoxide exerted excellent antibacterial effects through tight membrane wrapping and induction of lipid peroxidation. The wound-healing property of the erGO nanofilm was evaluated via treatments of wounds infected by Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), which not only killed bacteria but also accelerated wound healing in mice with a skin infection. The novel erGO nanofilm with dual antimicrobial mechanisms might serve as a promising multifunctional antimicrobial agent for medical wound dressing with high biocompatibility.