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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. While there is currently no cure for AD, several pharmacotherapeutic targets and management strategies have been explored. Additionally, traditional medicinal plants have gained attention for their potential role in AD management. Pharmacotherapeutic targets in AD include amyloid-beta (Aβ) aggregation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and cholinergic dysfunction. Traditional medicinal plants, such as Ginkgo biloba, Huperzia serrata, Curcuma longa (turmeric), and Panax ginseng, have demonstrated the ability to modulate these targets through their bioactive compounds. Ginkgo biloba, for instance, contains flavonoids and terpenoids that exhibit neuroprotective effects by reducing Aβ deposition and enhancing cerebral blood flow. Huperzia serrata, a natural source of huperzine A, has acetylcholinesterase-inhibiting properties, thus improving cholinergic function. Curcuma longa, enriched with curcumin, exhibits anti-inflammatory and antioxidant effects, potentially mitigating neuroinflammation and oxidative stress. Panax ginseng's ginsenosides have shown neuroprotective and anti-amyloidogenic properties. The investigation of traditional medicinal plants as a complementary approach to AD management offers several advantages, including a lower risk of adverse effects and potential multi-target interactions. Furthermore, the cultural knowledge and utilization of these plants provide a rich source of information for the development of new therapies. However, further research is necessary to elucidate the precise mechanisms of action, standardize preparations, and assess the safety and efficacy of these natural remedies. Integrating traditional medicinal-plant-based therapies with modern pharmacotherapies may hold the key to a more comprehensive and effective approach to AD treatment. This review aims to explore the pharmacotherapeutic targets in AD and assess the potential of traditional medicinal plants in its management. [ABSTRACT FROM AUTHOR]

The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC50 = 0.062 µM; BChE, IC50 = 1.482 µM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Aβ aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines. [ABSTRACT FROM AUTHOR]

Novel hybrids N-(4-phenoxybenzyl)aniline were designed, synthesized, and evaluated for their potential AChE inhibitory activity along with antioxidant potential. The inhibitory potential (IC 50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the tested compounds, 42 with trimethoxybenzene substituent showed maximum hAChE inhibition with the competitive type of enzyme inhibition (IC 50 = 1.32 µM; Ki = 0.879 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed favorable BBB permeability by most of the synthesized compounds. Meanwhile, compound 42 also inhibited AChE-induced Aβ aggregation (39.5–66.9%) in thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 42. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 42 in brain homogenates. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Biphenyl-3-oxo-1,2,4-triazine linked piperazines were designed and synthesized. • Compound 6g significantly inhibited the AChE and showed good CNS permeability. • In vivo studies showed significant improvement in learning and memory. • Biochemical analysis showed potential antioxidant property by compound 6g. Abstract A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC 50 ; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC 50 : 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (P e (exp) , 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE. [ABSTRACT FROM AUTHOR]

Abstract The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N -benzylpiperidine analogs (17 – 31 and 32 – 46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 μM. Meanwhile, both these compounds inhibited self- and AChE-induced Aβ aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aβ aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aβ 1-42 -induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies. Graphical abstract Image 1 Highlights • Design and synthesis of a series of N -benzylpiperidine analogs (17 – 46). • Compounds 25, 26, 40, and 41 exhibited balanced inhibition of AChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 40 and 41. • Biochemical analysis of rat brain homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. [ABSTRACT FROM AUTHOR]

Highlights • The pathophysiological roles and underlying mechanisms of several hypotheses involved in AD are extensively reviewed. • A detailed investigation of all the conventional and novel therapeutic targets. • The identification of structural and functional motifs with a comprehensive framework of the active sites involved. • To elucidate and simplify the complexity and call for attention on the crucial areas to discover innovative therapeutics. Abstract AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aβ, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors. [ABSTRACT FROM AUTHOR]

• In-silico based virtual screening of a library (Drug Central Database) containing 4199 FDA approved drugs; MM/GBSA and MD simulation analysis were performed. • Novel structurally modified propamidine derivatives were synthesized, characterized and tested for their anti-AD activity. • Compound 27 was a well-balanced and promising multi-targeting agent. • Compound 27 exhibited good self and AChE-induced Aβ aggregation inhibition in thioflavin T assay. • Compound 27 displayed significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. The use of multifunctional agents could act as a crucial strategy in the management of neurodegenerative disorders like Alzheimer's disease (AD). In search of multitargeted directed ligands for the treatment of AD, a drug repositioning study has been performed using In silico tools. Virtual screening of a library (Drug Central Database) containing 4199 FDA-approved drugs was utilized for the purpose, and denopamine, guanethidine, and propamidine were identified as hits to target both acetylcholinesterase (AChE) and β-secretase (BACE-1). Further, MM/GBSA and MD simulation analysis was also performed which suggested that propamidine, an antibacterial and antifungal drug , may become a crucial pharmacophore to design multi-target directed ligands for AD therapy. Finally, a series of structurally modified derivatives of propamidine by replacement of terminal amidines with substituted benzamide and acetamide moiety on both ends were synthesized, characterized, and tested for their anti-AD action. Compound 27 of the structurally modified series of propamidine has shown significant in vitro hAChE and hBACE-1 inhibition at submicromolar concentration range (hAChE: IC 50 = 0.832 ± 0.05 µM and hBACE-1: IC 50 = 0.428 ± 0.036 µM). Compounds 27 has also shown significant propidium iodide displacement from the PAS binding region and exhibited good self and AChE-induced Amyloid-β (Aβ) aggregation inhibition in thioflavin T assay. The in-vivo behavioral studies of compound 27 displayed significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel 4, 5-diphenyl-1 H -imidazole linked piperazine hybrids were rationally designed. • Compound 6f was a well-balanced and promising multi-targeting agent. • Compound 6f showed good propidium iodide displacement. • compound 6f (10 mg/kg) showed a statistically non-significant difference in % spontaneous alterations The multi-targeted organized strategy provides effectual and significant results to cure progressive neurodegenerative diseases like AD. Treatment for this awful disease is in infancy till now. A series of novel 4, 5-diphenyl-1 H -imidazole linked piperazine hybrids (6a-g and 7a-g) were synthesized by utilizing the concept of bio-isosteric replacement and hybrid pharmacophore approaches. The targeted compounds were identified by spectroscopic techniques and assessed for in vitro cholinesterase, BACE-1 inhibition, propidium iodide displacement, and Aβ disaggregation activities. Within the targeted inhibitors, 6f exhibited the most significant and inhibitory capacity against eeAChE (IC 50 = 0.416 ± 0.018 μM), eqBChE (IC 50 = 0.474 ± 0.054 μM), and BACE-1 (IC 50 = 0.392 ± 0.021 μM) targets. Propidium iodide displacement showed that compound 6f could be effectively linked with AChE's PAS (10 μM = 29.09 %, 50 μM = 41.43%). It showed inhibitory potential against both self (21.28 to 30.85%) and AChE-induced (25.70 to 51.07%) Aβ aggregation in thioflavin T assay. Moreover, the most active compound 6f was evaluated by performing in vivo behavioural studies with the help of the scopolamine-induced Y-maze model. The in vitro and in vivo in collaboration with in silico molecular docking and molecular dynamics simulation leads to ascertain the active site interaction of compound 6f with AChE and BACE-1. [ABSTRACT FROM AUTHOR]

The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC 50 = 0.054 μM), butyrylcholinesterase (hBChE, IC 50 = 0.787 μM) and beta-secretase-1 (hBACE-1, IC 50 = 0.098 μM). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki = 0.030 μM). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Aβ-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49 , with good oral absorption characteristics ascertained by pharmacokinetic studies. Image 1 • Design and synthesis of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles hybrids. • Compounds 48 and 49 exhibited balanced inhibition of AChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 48 and 49. • Ex vivo study of rat hippocampal homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. [ABSTRACT FROM AUTHOR]