Potential Multifunctional Agents Research Articles

Discovery of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones as balanced multifunctional agents against Alzheimer's disease

Based on previous work, a series of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones derivatives were identified as potential multifunctional therapeutic agents for Alzheimer's disease. Biological evaluation exhibited that these derivatives had great performance against MAO-B, Aβ1-42 aggregation, oxidative stress and metal ion dyshomeostasis. Among them, 10x was selected as the optimal agent for its excellent MAO-B inhibitory activity (IC50 = 0.41 μM, SI > 24.4), good antioxidant activity (1.16 Trolox equivalent) and anti-Aβ aggregation activity (56.03% and 57.51% for inhibition of self- and Cu2+-induced Aβ1-42 aggregation; 81.91% and 82.40% for disaggregation of self- and Cu2+-induced Aβ1-42 fibrils at 25.0 μM). Besides, 10x also exhibited obvious metal-ion chelating ability, anti-neuroinflammation (NO, TNF-α), neuroprotective activity and BBB permeability. More importantly, in vivo behavioral assessment demonstrated 10x could remarkably improve the memory and cognitive impairment in Aβ1-42 induced AD mice model. Overall, these test results indicated 10x could serve as a balanced multifunctional anti-AD agent and deserved further research.

2-Hydroxy-4-benzyloxylimine Resveratrol Derivatives as Potential Multifunctional Agents for the Treatment of Parkinson's Disease.

A series of 2-hydroxy-4-benzyloxylimine resveratrol derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of Parkinson's disease. The results revealed that most derivatives possessed good multifunctional activities. Among them, representative compound (E)-5-[(4-fluorobenzyl)oxy]-2-{[(4-hydroxyphenyl)imino]methyl}phenol (7 h) exhibited excellent MAO-B inhibition (IC50 =8.43×10-3 μM) and high antioxidant activity (ORAC=3.45 Trolox equivalent). Additionally, 7 h displayed good metal chelating ability, appropriate blood-brain barrier (BBB) permeability, significant neuroprotective effect, and great anti-neuroinflammatory activity. Furthermore, 7 h can also ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease symptoms in mice. Therefore, compound 7 h was found to be a promising candidate for further development against PD.

Discovery of novel 2-hydroxyl-4-benzyloxybenzyl aniline derivatives as potential multifunctional agents for the treatment of Parkinson's disease

To discover novel multifunctional agents for the treatment of Parkinson's disease, a series of 2-hydroxyl-4-benzyloxybenzyl aniline derivatives was designed, synthesized and evaluated. The biological screening indicated that representative compound 6h possessed excellent MAO-B inhibition (IC50 = 0.014 μM), high antioxidant activity (ORAC = 2.14 Trolox equivalent), good metal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Additionally, 6h exhibited great ability to alleviate the neuroinflammtion by suppressing the activation of NF-κB pathway in vitro. Furthermore, 6h can also ameliorate MPTP induced Parkinson's disease symptoms in mice by improving the dopamine level and repressing oxidative damage. These results indicated that compound 6h was a promising candidate for further development against PD.

Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies

Alzheimer’s disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC50 = 0.87 μM) and huBuChE (IC50 = 3.3 μM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-α production, and significantly inhibited self-mediated Aβ1-42 aggregation (60.6%) and huAChE-mediated induced Aβ1-40 aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Aβ1-42-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [11C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations.

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

Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease.

New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC50 to 0.224 μM) and butyrylcholinesterase (BChE, IC50 to 0.0104 μM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug‐drug interactions in clinical use. The conjugates were mixed‐type reversible inhibitors of both cholinesterases and demonstrated dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking that, along with experimental results on propidium iodide displacement, suggest their potential to block AChE‐induced β‐amyloid aggregation. The new conjugates exhibited high ABTS.+‐scavenging activity. N‐(6‐(1,2,3,4‐Tetrahydroacridin‐9‐ylamino)hexyl)salicylamide is a lead compound that also demonstrates metal chelating ability toward Cu2+, Fe2+ and Zn2+. Thus, the new conjugates have displayed the potential to be multifunctional anti‐AD agents for further development.

Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors\u200f on PC12 cells

BackgroundThe loss of cholinergic neurotransmission in Alzheimer's disease (AD) patients' brain is accompanied by a reduced concentration of Acetylcholine (ACh) within synaptic clefts. Thus, the use of acetylcholinesterase inhibitors (AChEIs) to block the cholinergic degradation of ACh is a promising approach for AD treatment. In the present study, a series of 2-chloro-3-hydrazinopyrazine derivatives (CHP1-5) were designed, synthesized, and biologically evaluated as potential multifunctional anti-AD agents.MethodsIn addition, the chemical structures and purity of the synthesized compounds were elucidated through using IR, 1H and 13C NMR, and elemental analyses. Further, the intended compounds were assessed in vitro for their AChE inhibitory and neuroprotective effects. Furthermore, DPPH, FRAP and ABTS assays were utilized to determine their antioxidant activity. The statistical analysis was performed using one-way ANOVA.ResultsBased on the results, CHP4 and CHP5 exhibited strong AChE inhibitory effects with the IC50 values of 3.76 and 4.2 µM compared to the donepezil (0.53 µM), respectively. The study examined the effect and molecular mechanism of CHP4 on the Ab1–42-induced cytotoxicity in differentiated PC12 cells. At concentrations of 0–100 μM, CHP4 was non-toxic in PC12. Additionally, Ab1–42 significantly stimulated tau hyperphosphorylation and induced differentiated PC12 cell death. Further, CHP4 resulted in diminishing the Ab1–42-induced toxicity in PC12 cell significantly. CHP4 at 30 μM concentration significantly increased the Ab1–42-induced HSP70 expression and decreased tau hyperphosphorylation.ConclusionsAccording to the results of our studies CHP4 can be considered as safe and efficient AChEI and employed as a potential multifunctional anti-AD agent.

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer's Activity Profile.

Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC50(AChE) = 2.9–1.4 µM, IC50(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ42 aggregation. Conjugates 3 had no effect on Aβ42 self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents.

Novel Donepezil-Chalcone-Rivastigmine Hybrids as Potential Multifunctional Anti-Alzheimer's Agents: Design, Synthesis, in Vitro Bilogical Evaluation, in Silico Study, Molecular Dynamics Simulation, Druggability, PET-CT Imaging Analysis and in Vivo Study

Novel Donepezil-Chalcone-Rivastigmine Hybrids as Potential Multifunctional Anti-Alzheimer's Agents: Design, Synthesis, in Vitro Bilogical Evaluation, in Silico Study, Molecular Dynamics Simulation, Druggability, PET-CT Imaging Analysis and in Vivo Study

Silk Embolic Material for Catheter-Directed Endovascular Drug Delivery.

Embolization is a catheter-based minimally invasive procedure that deliberately occludes diseased blood vessels for treatment purposes. A novel silk-based embolic material (SEM) that is developed and optimized to provide tandem integration of both embolization and the delivery of therapeutics is reported. Natural silk is processed into fibroin proteins of varying lengths and is combined with charged nanoclay particles to allow visibility and injectability using clinical catheters as small as 600 μm in diameter at lengths >100cm.SEMs loaded with fluorochrome labeled bovine albumin and Nivolumab, which is among the most used immunotherapy drugs worldwide, demonstrate a sustained release profile in vitro over 28 days. In a porcine renal survival model, SEMs with labeled albumin and Nivolumab successfully embolize porcine arteries without recanalization and lead to the delivery of both albumin and Nivolumab into the interstitial space of the renal cortex. Mechanistically, it is shown that tissue delivery is most optimal when the internal elastic membrane of the embolized artery is disrupted. SEM is a potential next-generation multifunctional embolic agent that can achieve embolization and deliver a wide range of therapeutics to treat vascular diseases including tumors.

Design, Synthesis, and Evaluation of Chalcone Derivatives as Multifunctional Agents against Alzheimer's Disease.

Fifteen chalcone derivatives 3a-3o were synthesized, and evaluated as multifunctional agents against Alzheimer's disease. In vitro studies revealed that these compounds inhibited self-induced Aβ1-42 aggregation effectively ranged from 45.9-94.5 % at 20 μM, and acted as potential antioxidants. Their structure-activity relationships were summarized. In particular, (2E)-3-[4-(dimethylamino)phenyl]-1-(pyridin-2-yl)prop-2-en-1-one (3g) exhibited an excellent inhibitory activity of 94.5 % at 20 μM, and it could disassemble the self-induced Aβ1-42 aggregation fibrils with ratio of 57.1 % at 20 μM concentration. In addition, compound 3g displayed good chelating ability for Cu2+ , and could effectively inhibit and disaggregate Cu2+ -induced Aβ aggregation. Moreover, compound 3g exerted low cytotoxicity, significantly reversed Aβ1-42 -induced SH-SY5Y cell damage. More importantly, compound 3g remarkably ameliorated scopolamine-induced memory impairment in mice. In summary, all the results revealed compound 3g was a potential multifunctional agent for AD therapy.

Design, synthesis and biological evaluation of naringenin carbamate derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease

A series of naringenin derivatives were designed and synthesized as multifunctional anti-Alzheimer’s disease (AD) agents. The results showed that these derivatives displayed moderate-to-good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities at the micromolar range (IC50, 12.91 ~ 62.52 μM for AChE and 0.094 ~ 13.72 μM for BuChE). Specifically, compound 1 showed the highest inhibitory activity against BuChE with the IC50 value of (0.094 ± 0.0054) μM. A Lineweaver-Burk plot and molecular docking studies demonstrated that 1 targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of BuChE. Besides, all derivatives showed excellent hydroxyl free radicals (·OH) scavenging ability than vitamin C and cyclic voltammetry results displayed that 1 could effectively scavenge superoxide anion radical (·O2–). In addition, compound 1 displayed good metal chelating properties and had anti-Aβ aggregation activities. Therefore, compound 1 might be the potential anti-AD agent for further developments.

Trifunctional Graphene Quantum Dot@LDH Integrated Nanoprobes for Visualization Therapy of Gastric Cancer (Adv. Healthcare Mater. 16/2021)

Nanoprobes In article number 2100512 by Yechang Qian, Shilong Wang, and co-workers, trifunctional LDH@SGQD-VP16 integrated nanoprobes are composed of layered double hydroxides (LDHs), sulfur-doped graphene quantum dots (SGQDs) with stable fluorescence, and etoposide (VP16). Which can simultaneously achieve targeted aggregation, fluorescence visualization, and chemotherapy. This work provides a theoretical and experimental basis for LDH@SGQD-VP16 as a potential multifunctional agent for visualization therapy of gastric cancer.

Trifunctional Graphene Quantum Dot@LDH Integrated Nanoprobes for Visualization Therapy of Gastric Cancer.

Visualization technology has become a trend in tumor therapy in recent years. The superior optical properties of graphene quantum dots (GQDs) make them suitable candidates for tumor diagnosis, but their tumor targeting and drug-carrying capacities are still not ideal for treatment. Sulfur-doped graphene quantum dots (SGQDs) with stable fluorescence are prepared in a previous study. A reliable strategy by associating layered double hydroxides (LDHs) and etoposide (VP16) is designed for precise visualization therapy. Trifunctional LDH@SGQD-VP16 integrated nanoprobes can simultaneously achieve targeted aggregation, fluorescence visualization, and chemotherapy. LDH@SGQD-VP16 can accumulate in the tumor microenvironment, owing to pH-sensitive properties and long-term photostability in vivo, which can provide a basis for cancer targeting, real-time imaging, and effect tracking. The enhanced therapeutic and attenuated side effects of VP16 are demonstrated, and the apoptosis caused by LDH@SGQD-VP16 is ≈2.7 times higher than that of VP16 alone, in HGC-27 cells. This work provides a theoretical and experimental basis for LDH@SGQD-VP16 as a potential multifunctional agent for visualization therapy of gastric cancer.

Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 μM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

Design, synthesis, and in vitro evaluation of 4-aminoalkyl-1(2H)-phthalazinones as potential multifunctional anti-Alzheimer’s disease agents

A series of 4-aminoalkyl-1(2H)-phthalazinone derivatives was designed and synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. In vitro biological assay results demonstrated that most synthesized compounds exhibited significant AChE inhibition, moderate to high MAOs inhibitory potencies and good anti-platelet aggregation abilities. Among them, compound 15b exhibited the highest inhibitory potencies towards MAO-B and MAO-A (IC50 = 0.7 µM and 6.4 µM respectively), moderate inhibition towards AChE (IC50 = 8.2 µM), and good activities against self- and Cu2+-induced Aβ1–42 aggregation and platelet aggregation. Moreover, 15b also displayed antioxidant capacity, neuroprotective potency, anti-neuroinflammation and BBB permeability. These excellent results indicated that compound 15b could be worthy of further studies to be considered as a promising multifunctional candidate 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.

Novel 3-benzylidene/benzylphthalide Mannich base derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease

To discover novel multifunctional agents for the treatment of Alzheimer’s disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC50 = 9.18 × 10−5 and 6.16 × 10−4 μM, respectively), good MAO-B inhibitory activity (IC50 = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency, disaggregation ability on Aβ1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.

Effects of agmatine and red wine concentrate, enriched with polyphenolic compounds, on L-arginine / nitrogen oxide system in the brain of rats with experimental diabetes mellitus

Background. Diabetes mellitus is a chronic endocrine metabolic disease with absolute or relative insufficiency of insulin, accompanied by impaired metabolism. Endogenous bioamine agmatine may become a basis of new antidiabetic drugs, as it is capable to induce the release of some peptide hormones, in particular insulin, and can regulate NO synthesis. Natural polyphenols are potential multifunctional agents that also can reduce the risk of diabetes and diabetic complications. The aim of the study was to evaluate the effect of agmatine and red wine concentrate, enriched with polyphenolic compounds, on NO-synthase activity and the content of NO stable metabolites under experimental diabetes mellitus. Materials and Methods. The experiments were conducted on white Wistar male rats. Diabetes was induced by intra-abdominal injection of streptozotocin. From the 14th day after the induction of diabetes, agmatine was injected intramuscularly or red wine concentrate, enriched with polyphenolic compounds was administrated orally to animals for 14 days. Rats were decapitated under ether anesthesia on the 28th day of the experiment. In the brain of rats, the activity of constitutive (Ca2+-dependent) and inducible (Ca2+-independent) isoforms of NO-synthase and the content of nitrite and nitrate anions were determined. Results and Discussion. The activities of constitutive and inducible isoforms of NO-synthase were increased in the brain of diabetic rats. The administration of both agmatine and red wine concentrate, enriched with polyphenolic compounds, caused the reduction of the activities of NO-synthase isoforms. In the case of diabetes, the administration of agmatine contributes to the increase of nitrite and nitrate content in brain cells compared to diabetes. The administration of red wine concentrate, enriched with polyphenolic compounds, also promotes nitrite levels but does not affect the nitrate level. Conclusion. We found that the red wine concentrate, enriched with polyphenolic compounds, has a stronger effect on the activity of Ca2+-dependent and Ca2+-independent isoforms of NO-synthase, as well as the content of nitrites and nitrates in brain of rats with experimental diabetes mellitus, compared to the effect of agmatine.

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020.

Dementia is a term used to define different brain disorders that affect memory, thinking, behavior, and emotion. Alzheimer's disease (AD) is the second cause of dementia that is generated by the death of cholinergic neurons (especially acetylcholine (ACh)), which have a vital role in cognition. Acetylcholinesterase inhibitors (AChEI) affect acetylcholine levels in the brain and are broadly used to treat Alzheimer's. Donepezil, rivastigmine, and galantamine, which are FDA-approved drugs for AD, are cholinesterase inhibitors. In addition, scientists are attempting to develop hybrid molecules and multi-target-directed ligands (MTDLs) that can simultaneously modulate multiple biological targets. This review highlights recent examples of MTDLs and fragment-based strategy in the rational design of new potential AD medications from 2010 onwards.