Potential Multifunctional Agents Research Articles

Synthesis and Biological Activity Assessment of 2-Styrylbenzothiazoles as Potential Multifunctional Therapeutic Agents.

A current trend in healthcare research is to discover multifunctional compounds, able to interact with multiple biological targets, in order to simplify multi-drug therapies and improve patient compliance. The aim of this work was to outline the growing demand for innovative multifunctional compounds, achieved through the synthesis, characterisation and SAR evaluation of a series of 2-styrylbenzothiazole derivatives. The six synthesised compounds were studied for their potential as photoprotective, antioxidant, antiproliferative, and anti-inflammatory agents. In order to profile antioxidant activity against various radical species, in vitro DPPH, FRAP and ORAC assays were performed. UV-filtering activity was studied, first in solution and then in formulation (standard O/W sunscreen containing 3% synthesised molecules) before and after irradiation. Compound BZTst6 proved to be photostable, suitable for broad-spectrum criteria, and is an excellent UVA filter. In terms of antioxidant activity, only compound BZTst4 can be considered a promising candidate, due to the potential of the catechol moiety. Both also showed exceptional inhibitory action against the pro-inflammatory enzyme 5-lipoxygenase (LO), with IC50 values in the sub-micromolar range in both activated neutrophils and under cell-free conditions. The results showed that the compounds under investigation are suitable for multifunctional application purposes, underlining the importance of their chemical scaffolding in terms of different biological behaviours.

Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads

Multi-functional cysteine-targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Herein, we present novel unsaturated and asymmetric ketone (oxazolinosene) scaffolds that selectively conjugate cysteine residues of peptides and bovine serum albumin under normal physiological conditions. This unsaturated saccharide depletes GSH in NCI-H1299 cells, leading to anti-tumor effects in vitro. The acetyl group of the ketal moiety on the saccharide ring can be converted to other carboxylic acids in a one-pot synthesis. In this way, the loaded acid can be click-released during cysteine conjugation, making the oxazolinosene a potential multifunctional therapeutic agent. The reaction kinetic model for oxazolinosene conjugation to GSH is well established and was used to evaluate oxazolinosene reactivity. The aforementioned oxazolinosenes were stereoselectively synthesized via a one-step reaction of nitriles with saccharides and conveniently converted into a series of α, β-unsaturated ketone N-glycosides as prevalent synthetic building blocks. The reaction mechanisms of oxazolinosene synthesis were investigated through calculations and validated with control experiments. Overall, these oxazolinosenes can be easily synthesized and developed as cysteine-targeted covalent warheads carrying useful click-releasing groups.

Design, Synthesis, and Invitro Pharmacological Evaluation of Novel Resveratrol Surrogate Molecules against Alzheimer's Disease.

A series of resveratrol surrogate molecules were designed, synthesized and biologically evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) along with anti-oxidant activity as potential novel multifunctional agents against Alzheimer's disease (AD). Six novel compounds were synthesized by reacting (E)-4-(3,5-Dimethoxystyryl) aniline with benzaldehyde and some selected derivatives of benzaldehyde in the presence of ethanol and a few drops of glacial acetic acid which followed the general scheme involved in the formation of Schiff bases. The spectral analysis data including FT-IR, 1H-NMR, 13C-NMR, and Mass spectroscopy results were found to be in good agreement with the newly synthesized compounds (Resveratrol Surrogate Molecules 1-6). The synthesized compounds were evaluated for their dual cholinesterase inhibitory activities, cytotoxic effect, and anti-oxidant potential. The results showed that compound RSM5 showed potent inhibitory activity against AChE and BChE. In, addition the cytotoxicity of the compound RSM5 is less and found to be within the desirable limit indicating the potential safety of RSM5. Also, it possesses substantial anti-oxidant activity which qualifies RSM5 as an anti-AD agent. Taken together, these findings demonstrate that the molecule RSM5 had the most multifunctional properties and could be a promising lead molecule for the future development of drugs for Alzheimer's treatments.

Crocus sativus (Saffron): A potential multifunctional therapeutic agent for neurodegenerative disorders.

Crocus sativus (Saffron): A potential multifunctional therapeutic agent for neurodegenerative disorders.

New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease: design, synthesis, and biological evaluation

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64–70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives’ significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration.

Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage- gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.

Donepezil-Squaric Acid Hybrid: Synthesis, Characterization and Investigation of Anticholinesterase Inhibitory, DNA Binding and Antioxidant Properties

A novel donepezil-squaric acid (DS) hybrid compound was designed, synthesized and biologically evaluated as multi-target-directed ligands against neurodegenerative disease by fusing a fragment of donepezil (D) and squaric acid (S). This study focuses on investigating the binding mechanism of double-stranded fish sperm DNA (Fsds-DNA) with DS and S. The interaction between DS and S with Fsds-DNA was explored using spectrophotometric and viscometric methods. Besides, DNA binding constants (Kb) were determined. The results reveal that DS binds to Fsds-DNA via the minor groove binding mode. The hybrid molecule demonstrates potent inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Furthermore, it exhibits significant antioxidant activity, surpassing the scavenging ability of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals compared to squaric acid alone. In conclusion, these results suggest that the hybrid molecule may serve as a potential multifunctional agent for the treatment of Alzheimer’s disease.

Multifunctional anti-Alzheimer's agents: Synthesis, biological evaluation, and molecular docking study of new 2-phenoxyacetamide/3-phenoxypropanamide/4-oxobutanamide derivatives

In the current study, three series of new compounds were designed and synthesized through hit optimization, based on the hit compound with a structure (E)-N-(4-{[benzyl(methyl)amino]methyl}thiazol-2-yl)-3-(3,4-dimethoxyphenyl)prop‑2-enamide, which was found as a potential multifunctional anti-Alzheimer agent in our previous study. Then, the biological activities of synthesized compounds (4a-c, 13a-b and 15a-c) were evaluated. The results indicated that 4b, a 2-phenoxyacetamide derivative, exhibited good multifunctional activities. Namely, compound 4b displayed better BChE inhibition (BChE IC50 = 2.10 µM) and antioxidant activity (ORAC = 1.18 Trolox equivalents) compared to the hit compound (BChE IC50 = 14.70 µM, ORAC = 0.5 Trolox equivalents). Additionally, 4b was able to chelate all tested biometals and it also exhibited a neuroprotective effect (63 %), comparable to reference ferulic acid (77 %) while maintaining its safety upon PC12 cell line. When it comes to lowering the levels of TNF-α, NO, IL-1β, and IL-6, 4b performed better activity, relative to the other synthesized compounds. Subsequently, in silico studies such as physicochemical properties, density functional theory (DFT) computational approach and molecular docking studies were performed.

A recent update on huprine and its hybrids as a potential multifunctional agent for the treatment of Alzheimer's disease

AbstractAlzheimer's disease (AD) is a common age‐related neurodegenerative brain disorder characterized by the impairment in memory and other cognitive functions. Although there is currently no successful pharmacotherapy for AD, researchers are continuously exploring the various pathogenesis of AD to develop potential therapeutic drugs. Of the multiple hypotheses for AD, the cholinergic and amyloid‐β (Aβ) hypothesis are the main targeting hypothesis for AD. Some researchers proposed that the symptoms involved in AD (loss of memory, cognitive impairment, and amnesia) are the main event linked to the cholinergic neurotransmitter (acetylcholine). Therefore, the development of AChE inhibitors to increase the level of ACh in the synaptic cleft can improve learning and memory in AD patients. Huprine X is a synthetic ChE inhibitor developed by the hybridization of Huperzine A and the synthetic drug tacrine. This review focuses on the last 10 year's literature search on huprine and its analogues for the treatment of AD. We expect that this review can be helpful for medicinal chemists, and neuro‐chemists to provide new ideas for the development of new drugs therapy for AD.

Argininyl-Fructosyl-Galactose: A Novel Amino Acid Derivative improves Cisplatin-induced Intestinal Toxicity via Reactive Oxygen Species- mediated Apoptosis Pathway.

Based on the Maillard reaction principle of red ginseng, this study innovatively synthesized a new amino acid derivative by combining arginine with lactose through simulated synthesis and was separated and purified through repeated silica gel and polyacrylamide gel (Bio-gel P-II) column chromatography. The work was aimed at elucidating the synthesis of a novel amino acid derivative and investigating the intestinal protective activity of the novel amino acid derivative and possible molecular mechanism by establishing the intestinal injury model induced by cisplatin in mice. The purity and molecular weight of the amino acid derivatives were determined to be by electrospray ionization mass spectrometry (ESI-MS). Subsequently, by establishing cisplatin (20 mg/kg)-induced intestinal injury in vivo for 10 days and IEC-6 cell model. The biochemical indexes and histopathological analysis were used to evaluate the oxidative stress and inflammatory and pathological changes of intestinal tissue in mice. The protein expression levels of p-Nuclear transcription factor-κB (p-NF-κB), cleaved caspase 3/caspase 3, cleaved caspase 9/caspase-9, Bcl-2, Bax, cytochrome C, phosphatidylinositol 3-kinase (PI3K), Protein Kinase B (Akt), p-PI3K, p-Akt were quantified through immunofluorescence staining and western blot analysis. The new amino acid derivatives of chemical structure were identified to be 1- (arginine-Nαgroup)-1-deoxy-4-O-(β-D-galactopyranosyl)-D-fructose, named Argininylfructosyl- galactose (AFGA, C18H34N4O12). The results showed that pretreatment with a single AFGA dose remarkably alleviated cisplatin-evoked intestinal oxidative stress injury, and the levels of reactive oxygen species (ROS) were lessening in IEC-6 cells (p<0.05, p<0.01) and could effectively reduce the secretion of TNF-α and IL-1β in serum and the expression level of NF-κB protein in intestinal tissues (p<0.01). Meantime, AFGA also significantly suppressed the caspase 3, caspase 9, cytochrome C and Bax protein expression in intestinal tissue in mice (p<0.01), and regulated the PI3K/Akt pathway (p<0.05, p<0.01). Importantly, the molecular docking results of AFGA also suggested a better binding ability with the above-mentioned related target proteins. The results clearly revealed AFGA as a potential multifunctional therapeutic agent with a clear protective effect against cisplatin-induced intestinal injury may be related to the PI3K/Akt signaling pathway.

Phenylstyrylpyrimidine derivatives as potential multipotent therapeutics for Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological disorder that affects millions of people worldwide. Despite extensive research efforts, there are currently no effective disease-modifying therapeutics available for the complete cure of AD. In the current study, we have designed and synthesized a series of phenyl-styryl-pyrimidine derivatives as potential multifunctional agents against different targets of AD. The compounds were evaluated for their ability to inhibit acetylcholinesterase (AChE), monoamine oxidase (MAO) and β amyloid aggregation which are associated with the initiation and progression of the disease. Several compounds in the series exhibited potent inhibitory activity against AChE and MAO-B, with IC50 values in the low micromolar range. In particular, two compounds, BV-12 and BV-14, were found to exhibit a multipotent profile and showed non-competitive inhibition against MAO-B with IC50 values of 4.93 ± 0.38 & 7.265 ± 0.82 μM, respectively and AChE inhibition with IC50 values of 7.265 and 9.291 μM, respectively. BV-12 and BV-14 also displayed β amyloid self-aggregation inhibition of 32.98% and 23.25%, respectively. Furthermore, molecular modelling studies revealed that BV-14 displayed a docking score of -11.20 kcal mol-1 with MAO-B & -6.767 kcal mol-1 with AChE, forming a stable complex with both proteins. It was concluded that phenyl-styryl-pyrimidine derivatives have the potential to be developed as multitarget directed ligands for the treatment of AD.

The hybrid nanosystem for the identification and magnetic hyperthermia immunotherapy of metastatic sentinel lymph nodes as a multifunctional theranostic agent.

Lymphatic metastasis is the main cause of early-stage tumor spread, making the identification and therapy of metastatic sentinel lymph nodes (SLNs) are highly desirable in clinic. Currently, suspected malignant SLNs typically undergo a series of independent operations in clinical practice, including imaging, staining, sentinel lymph node biopsy (SLNB) and lymph node dissection (LND), which brings inconvenience to diagnosis and treatment, and may cause postoperative complications for patients. Moreover, the ordinary removal of tumor-draining lymph nodes (TDLNs) may do harm to systemic immunity required for tumor eradication. Hence, we utilized the hybrid nanosystem (SPIOs + RPPs) we constructed before for the integrated staining, ultrasound imaging, and therapy of metastatic SLNs. In this study, SPIOs + RPPs could migrate into SLNs successfully to stain them black for easy visual identification. Beyond staining, the hybrid nanosystem could realize contrast enhanced ultrasound (CEUS) imaging in SLNs. Meanwhile, it could inhibit cancer cells to lower the tumor burden and reverse immune-suppressive microenvironment of metastatic SLNs effectively via magnetic hyperthermia immunotherapy in VX2 tumor-bearing rabbits with popliteal fossa lymph node metastasis. These findings indicate that SPIOs + RPPs is a potential multifunctional theranostic agent for detection and therapy of lymphatic metastasis.

Treatment of rheumatoid arthritis with dissymmetric fluorine and pyridyl-substituted 3,5-bis(aryl)-4-piperidone derivatives by inhibition of NF-κB and MAPK activation

Inhibition of inflammation-related NF-κB and MAPK activation could treat rheumatoid arthritis (RA). Previously, some fluorine-substituted 3,5-bis(aryl)-4-piperidone derivatives (BAPs) exhibited promising anti-inflammatory activity. Herein, interesting structural optimization was carried out and generated thirty-eight dissymmetric fluorine and pyridyl-substituted BAPs (4a-s and 5a-s). They were confirmed by NMR and HRMS. A preliminary structure–activity relationship was summarized and discovered 3,5-CF3 and 3-pyridyl-substituted 4k exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 4k inhibited Lipopolysaccharide-induced nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) activation by suppressing LPS-induced phosphorylation levels of NF-κB/p65, NF-κB/IκBα, c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases (ERK), and NF-κB/p38 in RAW264.7 cells. In vivo, 4k inhibited the development of inflammation and synovial proliferation in rat joint tissues, significantly decreasing paw swelling and arthritis index in adjuvant-induced arthritis rats. More importantly, 4k did not affect body weight and splenic index values. Overall, 4k showed optimistic anti-RA effects, which may be developed as a potential multifunctional agent for the clinical treatment of RA.

Promising 8-Aminoquinoline-Based Metal Complexes in the Modulation of SIRT1/3-FOXO3a Axis against Oxidative Damage-Induced Preclinical Neurons.

The discovery of novel bioactive molecules as potential multifunctional neuroprotective agents has clinically drawn continual interest due to devastating oxidative damage in the pathogenesis and progression of neurodegenerative diseases. Synthetic 8-aminoquinoline antimalarial drug is an attractive pharmacophore in drug development and chemical modification owing to its wide range of biological activities, yet the underlying molecular mechanisms are not fully elucidated in preclinical models for oxidative damage. Herein, the neuroprotective effects of two 8-aminoquinoline-uracil copper complexes were investigated on the hydrogen peroxide-induced human neuroblastoma SH-SY5Y cells. Both metal complexes markedly restored cell survival, alleviated apoptotic cascades, maintained antioxidant defense, and prevented mitochondrial function by upregulating the sirtuin 1 (SIRT1)/3-FOXO3a signaling pathway. Intriguingly, in silico molecular docking and pharmacokinetic prediction suggested that these synthetic compounds acted as SIRT1 activators with potential drug-like properties, wherein the uracil ligands (5-iodoracil and 5-nitrouracil) were essential for effective binding interactions with the target protein SIRT1. Taken together, the synthetic 8-aminoquinoline-based metal complexes are promising brain-targeting drugs for attenuating neurodegenerative diseases.

Panaxadiol carbamate derivatives: Synthesis and biological evaluation as potential multifunctional anti-Alzheimer agents

It is reported that panaxadiol has neuroprotective effects. Previous studies have found that compound with carbamate structure introduced at the 3-OH position of 20 (R) -panaxadiol showed the most effective neuroprotective activity with an EC50 of 13.17 μM. Therefore, we designed and synthesized a series of ginseng diol carbamate derivatives with ginseng diol as the lead compound, and tested their anti-AD activity. It was found that the protective effect of compound Q4 on adrenal pheochromocytoma was 80.6 ± 10.85 % (15 μM), and the EC50 was 4.32 μM. According to the ELISA results, Q4 reduced the expression of Aβ25-35 by decreasing β-secretase production. Molecular docking studies revealed that the binding affinity of Q4 to β-secretase was −49.67 kcal/mol, indicating a strong binding affinity of Q4 to β-secretase. Western blotting showed that compound Q4 decreased IL-1β levels, which may contribute to its anti-inflammatory effect. Furthermore, compound Q4 exhibits anti-AD activities by reducing abnormal phosphorylation of tau protein and activation of the mitogen activated protein kinase pathway. The learning and memory deficits in mice treated with Q4in vivo were significantly alleviated. Therefore, Q4 may be a promising multifunctional drug for the treatment of AD, providing a new way for anti-AD drugs.

Biosynthesis of gallic acid fabricated tellurium nanoparticles (GA-Te NPs) for enhanced antibacterial, antioxidant, and cytotoxicity applications

The development of antibiotic resistance and the onset of diverse forms of cancer necessitate the utilization of innovative multifunctional biocompatible materials. The synthesis of metal and metalloid nanoparticles through eco-friendly means demonstrates promising potential in therapeutic and diagnostic domains. Among these materials, Tellurium (Te) exhibits exceptional characteristics and finds application in numerous fields; nevertheless, its usage in biological applications has been somewhat limited, primarily due to its inherent toxicity. Furthermore, nanomaterials developed from Te have not garnered adequate research attention. Conversely, nanomaterials fashioned using biomolecules augment their biological efficacy and applicability. Therefore, the present work focuses on synthesizing the tellurium nanoparticles (Te NPs) using the antioxidant molecule gallic acid (GA) and evaluating their biological activity and toxicity for the first time. The study evidenced that GA-Te NPs are spherical and monodispersed, with an average size of 19.74 ± 5.3 nm. XRD analysis confirmed a hexagonal crystalline structure for GA-Te NPs, and FTIR analysis evidenced the capping of GA on Te NPs. GA-Te NPs (MIC: 1.56 μg/mL) strongly reduce the growth and biofilm formation of S. aureus, E. coli, and S. enterica. Additionally, GA-Te NPs at a concentration of 50 μg/mL cause a significant level of toxicity in BT474 breast cancer cells but not in NIH3T3 cells. Unexpectedly, GA-Te NPs at concentrations <250 μg/mL do not cause hemolysis in red blood cells (RBC) Besides, the way of utilizing the lower concentrations of therapeutics could result in ecological safety. Therefore, the study concludes that GA-Te NPs could be used as potential multifunctional agents.

Ganoderma lucidum methanolic extract as a potent phytoconstituent: characterization, in-vitro antimicrobial and cytotoxic activity

Ganoderma lucidum methanolic extract (GLME) has attracted tremendous attention due to its exceptional antimicrobial and anticancer properties that can be delicately tuned by controlling the initial extraction's content and concentration. Herein, we detailed the characterization, antimicrobial, and cytotoxic performance of GLME as a potential multi-functional therapeutic agent. Accordingly, FTIR, XRD, FESEM, EDX, and HPLC analyses were employed to assess the samples, followed by disc diffusion and microdilution broth methods to test its antibacterial effects against four Gram-positive and Gram-negative bacterial strains, viz., Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. MTT assay was applied to determine the cytotoxic activity of GLME against PDL and Hek-293 normal cell lines and MCF-7 and K-562 cancer cell lines. The IC50 values of 598 µg mL-1 and 291 µg mL-1 were obtained for MCF-7 and K-562 cancer cell lines, which confirmed the stronger anticancer activity of the GLME against blood cancer cells than breast cancer cells. This is while the IC50 of normal Hek-293 cells is 751 µg mL-1, and the lowest toxicity was observed for normal PDL cells with more than 57% survival at a concentration of 3000 µg mL-1. The results showed that the antibacterial property of this product against E.coli bacteria was higher than streptomycin, so the zone of inhibition was observed as 44 ± 0.09 mm and 30 ± 0.11 mm, respectively. These data provide valuable insights into the therapeutic usage of GLME for treating breast and blood cancers. This work is motivated by research studies looking for pharmacological products to address chronic and acute diseases, where further resources and studies are required to explore such products' adverse effects and toxicity.

Anticholinesterase and Serotoninergic Evaluation of Benzimidazole-Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease.

The etiology and pathogenesis of Alzheimer's disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dihydro-2-oxo-1H-benzimidazol-2-ones with their potential molecular targets: cholinesterases (ChE) and three types of the Gs-protein-coupled serotonin receptors (5-HTR) 5-HT6, 5-HT4 and 5-HT7 (5-HT4R, 5-HT6R and 5-HT7R, respectively). A microplate modification of the Ellman method was used for the biochemical analysis of the inhibitory ability of the drugs towards ChE. Molecular modeling methods, such as molecular docking and molecular dynamics (MD) simulation in water and the lipid bilayer, were used to study the interaction of the compounds with ChE and 5-HTR. In vitro experiments showed that the tested compounds had moderate anticholinesterase activity. With the help of molecular modeling methods, the mechanism of interaction of the tested compounds with ChE was investigated, the binding sites were described and the structural features of the drugs that determine the strength of their anticholinesterase activity were revealed. Primary in silico evaluation showed that benzimidazole-carboxamides effectively bind to 5-HT4R and 5-HT7R. The pool of the obtained data allows us to choose N-[2-(diethylamino)ethyl]-2-oxo-3-(tert-butyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride (compound 13) as the most promising for further experimental development.

Design, synthesis, and evaluation of new anti-inflammatory natural products amide derivatives endowed with anti-blood cancer activity towards development of potential multifunctional agents against hematological cancers

New amide derivatives of the natural product 5,6,7-trimethoxyflavanone were designed as multifunctional antiproliferative molecules against blood cancer and the associated inflammatory conditions. The targeted compounds were synthesized efficiently in three linear steps employing known chalcone starting materials. Compounds 2h, 2i, 2l, 2t, 2v and 2x having bromo or nitro substituted-phenyl rings elicited potential inhibitory effects on macrophages production of nitric oxide, PGE2 and TNF-α which are proinflammatory mediators involved in tumorigenesis and progression of blood cancer. Additionally, evaluation of direct inhibitory effects on the growth of diverse blood cancers including leukemia, lymphoma, and myeloma cell lines unveiled compound 2v as the most potential molecules eliciting at least five-folds the potency of the standard imatinib drug over the used diverse blood cancers. Furthermore, compound 2v showed good selectivity to blood cancer cells rather than normal MRC5 cells. Moreover, compound 2v triggered death of HL60 leukemia cells via apoptosis induction. In conclusion, the natural product-derived compound 2v might serve as a multifunctional lead compound for further development of agents for treatment of blood cancers.

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.