Alzheimer’s disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer’s disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aβ1–42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ1–42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.

Alzheimer's disease (AD) is a complex neurological disorder and multiple pathways are associated with its pathology. Currently available single-targeting drugs are found to be ineffective for the treatment of AD, and most of these drugs provide symptomatic relief. The multi-target directed ligand strategy is proposed as an effective approach for the treatment of AD. Herein, we report the design and synthesis of a series of 2-phenyl substituted chromone derivatives and their evaluation against AChE, MAO-B, and β amyloid self-aggregation inhibition. In the series, NS-4 and NS-13 were identified as the potent leads against all the specified targets. NS-4 and NS-13 exhibited balanced multipotent activities against AChE with IC50 values of 3.09 μM, and 0.625 μM and against MAO-B with IC50 values of 19.64 μM and 12.31 μM, respectively. These compounds also displayed 28.5% and 32.2% self-aggregation inhibition potential against Aβ1-42, respectively. All the compounds were found to be selective for AChE over BuChE. Additionally, NS-4 also exhibited potent BuChE inhibition with an IC50 value of 1.95 μM. Moreover, NS-4 and NS-13 reduced intracellular ROS levels up to 65% against SH-SY5Y cells at 25 μM concentration. The lead compounds were found to be neuroprotective and exhibited no cytotoxicity even at 25 μM concentration. In enzyme kinetic inhibition studies, these compounds showed mixed-type inhibition to AChE. In the computational studies, binding interactions, and orientations of the ligands at the active site of the enzymes were analyzed and these lead compounds were found to be thermodynamically stable inside the active cavity for up to 100 ns.

Alzheimer's disease (AD) is a complex neurological disorder without effective treatment. One factor in its development is c-Jun N-terminal kinases (JNKs), a type of protein related to brain function. JNK3, found mainly in the brain, contributes to AD by promoting brain abnormalities. Current research aims to create new JNK3 inhibitors for AD treatment using a virtual screening method. A database of compounds was filtered, and five potential compounds were identified with better scores than a reference. These compounds underwent simulations and energy calculations, showing stability and potential as JNK3 inhibitors.

An efficient metal-free single-step protocol has been developed for the direct synthesis of flavones from 2-hydroxyacetophenone and substituted benzaldehydes. This chemical transformation is exclusively promoted by the iodonium-triiodide ion couple formed through iodine and PEG-400 complexation. The triiodide anion not only helps in the abstraction of a proton from the acetophenone but also promotes the cyclization of intermediate chalcone to the corresponding flavones. The flavones were obtained in very high yields without using any toxic metal catalysts or harsh reaction conditions. The reaction mechanism was established through a series of test reactions and entrapping of reaction intermediates. The developed protocol provides direct access to flavones in high yields under milder reaction conditions with great substrate compatibility, including hydroxylated derivatives.

Alzheimer's disease (AD) is a progressive neurological disorder responsible for the cognitive dysfunction and cognitive impairment in the patients. Acetylcholinesterase inhibitors (AChEIs) are used to treat AD however, these only provided symptomatic relief and more efficient drug molecules are desired for the effective treatment of the disease. In this article, ligand-based drug-designing strategy was used to develop and validate a field-based 3D-QSAR pharmacophore model on quinazoline-based AChEIs reported in the literature. The validated pharmacophore model (AAAHR_1) was used as a prefilter to screen an ASINEX database via virtual screening workflow (VSW). The hits generated were subjected to MM-GBSA to identify potential AChEIs and top three scoring molecules (BAS 05264565, LEG 12727144 and SYN 22339886) were evaluated for thermodynamic stability at the target site using molecular dynamic simulations. Additionally, DFT study was performed to predict the reactivity of lead molecules towards acetylcholinesterase (AChE). Thus, by utilising various computational tools, three molecules were identified as potent AChEIs that can be developed as potential drug candidates for the treatment of AD.

Venous leg ulcers (VLUs) pose a growing healthcare challenge due to aging, obesity, and sedentary lifestyles. Despite various treatments available, addressing the complex nature of VLUs remains difficult. In this context, this study investigates repurposing boronated drugs to inhibit arginase 1 activity for VLU treatment. The molecular docking study conducted by Schrodinger GLIDE targeted the binuclear manganese cluster of arginase 1 enzyme (2PHO). Further, the ligand-protein complex was subjected to molecular dynamic studies at 500ns in Gromacs-2019.4. Trajectory analysis was performed using the GROMACS simulation package of protein RMSD, RMSF, RG, SASA, and H-Bond. The docking study revealed intriguing results where the tavaborole showed a better docking score (-3.957 Kcal/mol) compared to the substrate L-arginine (-3.379 Kcal/mol) and standard L-norvaline (-3.141 Kcal/mol). Tavaborole interaction with aspartic acid ultimately suggests that the drug molecule binds to the catalytic site of arginase 1, potentially influencing the enzyme's function. The dynamics study revealed the compounds' stability and compactness of the protein throughout the simulation. The RMSD, RMSF, SASA, RG, inter and intra H-bond, PCA, FEL, and MMBSA studies affirmed the ligand-protein and protein complex flexibility, compactness, binding energy, van der waals energy, and solvation dynamics. These results revealed the stability and the interaction of the ligand with the catalytic site of arginase 1 enzyme, triggering the study towards the VLU treatment.

Glycogen synthase kinase-3 beta (GSK-3 beta) plays pivotal role in regulating diverse range of cellular functions. It plays negative role in cellular signaling pathways and believed to involved in the pathologies of various diseases like neurological disorders, type II diabetes, inflammation, cardiac hypertrophy, cancer and bipolar disorders. GSK-3 beta is proposed as a promising target for drug discovery in treating these disease conditions. A number of structurally different chemical scaffolds including pyrimidinone derivatives have been identified as potential GSK-3 beta inhibitors. In the current study, PHASE module of Schrodinger 3D QSAR was used on about 157 pyrimidinone derivatives for the development of statistically significant PLS model. Consecutively, the best pharmacophore hypothesis with features like three hydrogen bond acceptors (A1-3), two hydrophobic regions (H1 and H2), and one aromatic ring (R1), was selected to screen ZINC and PUBCHEM databases. Molecules with matching pharmacophoric features and ROF were subjected to structure-based virtual screening (HTVS -> SP -> XP) and MMGBSA. Two hits from each library were selected for MD simulation studies that showed good pharmacokinetic properties, binding score (-6.8--8.8 kcal/mol) and Delta G(MMGBSA) (-55.80--58.1 kcal/mol) as compared to the reference molecule, NP-12. Similarly, MD simulation, and MMPBSA identified three compounds i. e. ZINC67743231, ZINC01582756, and PUBCHEM11553018 displaying stability in the binding pocket and demonstrated better binding affinity of -22.07, -27.33, and -30.61 kcal/mol, respectively, within the active site of GSK-3 beta. DFT studies also demonstrated the stability of these three lead compounds with a high energy gap between HOMO and LUMO ranging between 0.14546 and 0.1718 eV.

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 beta 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 mu M, respectively and AChE inhibition with IC50 values of 7.265 and 9.291 mu M, respectively. BV-12 and BV-14 also displayed beta 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. Alzheimer's disease (AD) is a multifactorial neurological disorder that affects millions of people worldwide.

A facile one-step catalyst free methodology has been developed for the regioselective functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions. Selectivity towards the O-regioisomer was achieved by using Cs2CO3 in DMF without use of any coupling reagents. A total of 14 regioselective O-alkylated 4,6-diphenylpyrimidines were synthesized in 81-91% yield. In the DFT studies it was observed that the transition state for the formation of the O-regioisomer is more favourable with Cs2CO3 as compared to K2CO3. Furthermore, this methodology was extended to increase the O/N ratio for the alkylation of 2-phenylquinazolin-4(3H)-one derivatives.

Zebrafish (Danio rerio) is currently in vogue as a prevalently used experimental model for studies concerning neurobehavioural disorders and associated fields. Since the 1960s, this model has succeeded in breaking most barriers faced in the hunt for an experimental model. From its appearance to its high parity with human beings genetically, this model renders itself as an advantageous experimental lab animal. Neurobehavioural disorders have always posed an arduous task in terms of their detection as well as in determining their exact etiology. They are still, in most cases, diseases of interest for inventing or discovering novel pharmacological interventions. Thus, the need for a harbinger experimental model for studying neurobehaviours is escalating. Ensuring the same model is used for studying several neuro-studies conserves the results from inter-species variations. For this, we need a model that satisfies all the pre-requisite conditions to be made the final choice of model for neurobehavioural studies. This review recapitulates the progress of zebrafish as an experimental model with its most up-to-the-minute advances in the area. Various tests, assays, and responses employed using zebrafish in screening neuroactive drugs have been tabulated effectively. The tools, techniques, protocols, and apparatuses that bolster zebrafish studies are discussed. The probable research that can be done using zebrafish has also been briefly outlined. The various breeding and maintenance methods employed, along with the information on various strains available and most commonly used, are also elaborated upon, supplementing Zebrafish's use in neuroscience.

The objective of this study is to recognize the potential traditional Chinese medicinal compound by virtual screening and docking analysis for the amyloid-beta disaggregation mechanism on Alzheimer's disease management. The selected target PDB ID: 1IYT was retrieved from protein data bank database. By uploading an optimized target structure in iScreen virtual screening tool, traditional Chinese medicinal compounds were shortlisted based on scoring functions. The resulted three common compounds were subjected to druglikeness, ADMET prediction and Autodock Vina analysis using Molinspiration, pkCSM and PyRx tool respectively. By considering all the results obtained in filter analysis, the ligand sanggenol A was shortlisted. The energy minimized ligand sanggenol A structure was docked against the optimized amyloid-beta peptide solution structure using Autodock 4.2.6 software. The binding energies for ten conformations of docked sanggenol A - beta amyloid complex is reported. Among ten conformations, three topmost conformations having better binding energies are interpreted with hydrophobic, hydrophilic, pi-pi and pi-cation interactions. Based on these scientific evidences, in silico study approach concludes that sanggenol A as a promising lead candidate which can be carried out for the further preclinical and clinical studies to prove for the management of Alzheimer's disease.

A simple, efficient, and practical metal-free protocol has been devised to synthesize imidazopyrido[3,4-b]indole-based fluorophores decorated with carbazole/β-carboline/pyridine scaffolds via three consecutive C–N bond formations in a single operation. A wide range of aromatic amines (2-aminopyridines, 3-aminocarbazole, and anilines) were successfully applied to synthesize the complex imidazolium ions. The significant features of this strategy include high efficiency, mild and environmentally benign reaction conditions, no chromatographic purification, and broad substrate scope with excellent yields of the isolated products. Moreover, excellent photophysical properties (ΦF up to 85%) were exhibited by these fluorophores.

Ligands binding to the colchicine domain of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in G2/M phase. A series of 4-Phenyl-1,2,3-triazole substituted pyrimidine deriva-tives have been synthesized and evaluated for antiproliferative and antitubulin activities. In the series, AV-6 and AV-14 were found to be active against the three tested cancer cell lines wherein AV-6 dis-played IC50 values of 1.2 mu M, 5.5 mu M, and 1.9 mu M while AV-14 displayed IC50 values of 4.7 mu M, 1.7 mu M, and 1.4 mu M against HCT-116, MCF-7 and HT-29 cell lines, respectively. These compounds were found to be non toxic to the normal cells (HEK-293). In the cell cycle analysis and JC-1 studies, these compounds induce mitocondria mediated apoptosis. In the tubulin polymerization inhibition studies, AV-6 displayed significant tubulin polymerization inhibition potential. In the molecular docking and simulation studies, these compounds fit well in the active site of colchicine. (C) 2022 Elsevier B.V. All rights reserved.

Aims: Development of anticancer agents targeting tubulin protein. Background: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. Objective: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. Methods: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. Result: ARV-2 with IC50 values of 3.16 μM, 5.31 μM, 10.6 μM against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. Conclusion: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents.

A series of morpholine substituted quinazoline derivatives have been synthesized and evaluated for cytotoxic potential against A549, MCF-7 and SHSY-5Y cancer cell lines. These compounds were found to be non-toxic against HEK293 cells at 25 μM and hence display anticancer potential. In these series compounds, AK-3 and AK-10 displayed significant cytotoxic activity against all the three cell lines. AK-3 displayed IC50 values of 10.38 ± 0.27 μM, 6.44 ± 0.29 μM and 9.54 ± 0.15 μM against A549, MCF-7 and SHSY-5Y cancer cell lines. Similarly, AK-10 showed IC50 values of 8.55 ± 0.67 μM, 3.15 ± 0.23 μM and 3.36 ± 0.29 μM against A549, MCF-7 and SHSY-5Y, respectively. In the mechanistic studies, it was found that AK-3 and AK-10 inhibit the cell proliferation in the G1 phase of the cell cycle and the primary cause of death of the cells was found to be through apoptosis. Thus, morpholine based quinazoline derivatives have the potential to be developed as potent anticancer drug molecules.

Alzheimer's disease (AD) is a multifactorial irreversible neurological disorder which results in cognitive impairment, loss of cholinergic neurons in synapses of the basal forebrain and neuronal death. Exact pathology of the disease is not yet known however, many hypotheses have been proposed for its treatment. The available treatments including monotherapies and combination therapies are not able to combat the disease effectively because of its complex pathological mechanism. A multipotent drug for AD has the potential to bind or inhibit multiple targets responsible for the progression of the disease like aggregated Aβ, hyperphosphorylated tau proteins, cholinergic and adrenergic receptors, MAO enzymes, overactivated N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor etc. The traditional approach of one disease-one target-one drug has been rationalized to one drug-multi targets for the chronic diseases like AD and cancer. Thus, over the last decade research focus has been shifted towards the development of multi target directed ligands (MTDLs) which can simultaneously inhibit multiple targets and stop or slow the progression of the disease. The MTDLs can be more effective against AD and eliminate any possibility of drug-drug interactions. Many important active pharmacophore units have been fused, merged or incorporated into different scaffolds to synthesize new potent drugs. In the current article, we have described various hypothesis for AD and effectiveness of the MTDLs treatment strategy is discussed in detail. Different chemical scaffolds and their synthetic strategies have been described and important functionalities are identified in the chemical scaffold that have the potential to bind to the multiple targets. The important leads identified in this study with MTDL characteristics have the potential to be developed as drug candidates for the effective treatment of AD.

Neurological disorders are disease conditions related to the neurons and central nervous system (CNS). Any structural, electrical, biochemical, and functional abnormalities in neurons can lead to various types of disorders, like Alzheimer’s disease (AD), depression, Parkinson’s disease (PD), epilepsy, stroke, etc. Currently available medicines are symptomatic and do not treat the disease state. Thus, novel CNS active agents with the potential to completely treat an illness are highly de-sired. A range of small organic molecules is being explored as potential drug candidates to cure dif-ferent neurological disorders. In this context, arylpiperazinehas been found to be a versatile scaffold and indispensable pharmacophore in many CNS active agents. Several molecules with arylpiperazine nucleus have been developed as potent leads for the treatment of AD, PD, depression, and other dis-orders. The arylpiperazine nucleus can be optionally substituted at different chemical structures and offer flexibility for the synthesis of a large number of derivatives. In the current review article, we have explored the role of various arylpiperazine containing scaffolds against different neurological disorders, including AD, PD, and depression. The structure-activity relationship studies were con-ducted for recognizing potent lead compounds. This review article may provide important insights into the structural requirements for designing and synthesizing effective molecules as curative agents for different neurological disorders.

Colchicine binding site represent a crucial target for the anticancer drug development especially in view of emerging drug resistance from the currently available chemotherapeutics. A total of 16 novel 4-N-heterocyclic-2aryl-6,7,8-trimethoxyquinazolines were synthesized and screened for antiproliferative and tubulin polymerization inhibition potential. The synthesized compounds were evaluated against MCF-7, HeLa and HT-29 cancer cell lines and normal cell line HEK-293 T. In the series, 2-aryl group with 4-bromophenyl substitution displayed IC50 values of 6.37 mu M, 17.43 mu M, 6.76 mu M and 4-chlorophenyl substitution displayed IC50 values of 2.16 mu M, 8.53 mu M, 10.42 mu M against MCF-7, HELA and HT29 cancer cell lines, respectively. In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, both the lead compounds were found to induce mitochondria mediated apoptosis and lead molecule with 4-chlorophenyl substitution displayed significant tubulin polymerization inhibition activity. In the computation studies, lead molecule displayed significant binding affinites in the colchicine domain and showed good thermodynamic stability during 100 ns MD simulation studies. 4-N-Heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines showed appreciable drug like characteristics and can be developed as potent anticancer agents.

A series of triphenyl substituted pyrimidines as analogous of colchicine and combretastatin A-4 was synthesized and evaluated for the antiproliferative potential. The compounds were screened against MDA-MB-231, HCT-116 and HT-29 cell lines using MTT assay. Most of the compounds displayed antiproliferative activity in low to sub micro molar concentration. Amongst the synthesized derivatives, compounds HK-2, HK-10 and HK-13 were found to be effective against all the three cancer cell lines. HK-2 exhibited IC50 values of 3.39 µM, 4.78 µM and 4.23 µM, HK-10 showed IC50 values of 0.81 µM, 5.89 µM, 4.96 µM and HK-13 showed IC50 values 3.24 µM, 4.93 µM and 4.73 µM against MDA-MB-231, HCT-116 and HT-29 cancer cell lines, respectively. HK-10 was found to be the most potent compound in the series with IC50 values of 0.81 µM against MDA-MB-231. In the cell cycle analysis, HK-2 and HK-10 showed cell arrest at G2/M phase of the cell cycle while HK-13 inhibited cell growth at the G1/G0 phase. All the three compounds showed cell death induced through apoptosis. In the docking studies, HK-2, HK-10 and HK-13 were found to fit well in the colchicine binding site of the tubulin. Some of the compounds in the current series were found to be promising against all the three cancer cell lines and may act as potent leads for further development.