Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N-methyl-d-aspartate (NMDA) receptor. However, the conventional therapy "one target, one molecule" has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies bearing different heterocycles, in vitro and in vivo activities of the compounds, and their corresponding structure–activity relationships. This knowledge will allow us to identify and design more effective MTDLs for the treatment of AD. 

A comprehensive review of multi-target directed ligands in the treatment of Alzheimer’s disease

Histamine performs dual roles as an immune regulator and a neurotransmitter in the mammalian brain. The histaminergic system plays a vital role in the regulation of wakefulness, cognition, neuroinflammation, and neurogenesis that are substantially disrupted in various neurodegenerative and neurodevelopmental disorders. Histamine H3 receptor (H3R) antagonists and inverse agonists potentiate the endogenous release of brain histamine and have been shown to enhance cognitive abilities in animal models of several brain disorders. Microglial activation and subsequent neuroinflammation are implicated in impacting embryonic and adult neurogenesis, contributing to the development of Alzheimer’s disease (AD), Parkinson’s disease (PD), and autism spectrum disorder (ASD). Acknowledging the importance of microglia in both neuroinflammation and neurodevelopment, as well as their regulation by histamine, offers an intriguing therapeutic target for these disorders. The inhibition of brain H3Rs has been found to facilitate a shift from a proinflammatory M1 state to an anti-inflammatory M2 state, leading to a reduction in the activity of microglial cells. Also, pharmacological studies have demonstrated that H3R antagonists showed positive effects by reducing the proinflammatory biomarkers, suggesting their potential role in simultaneously modulating crucial brain neurotransmissions and signaling cascades such as the PI3K/AKT/GSK-3β pathway. In this review, we highlight the potential therapeutic role of the H3R antagonists in addressing the pathology and cognitive decline in brain disorders, e.g., AD, PD, and ASD, with an inflammatory component. 

Targeting Microglia in Neuroinflammation: H3 Receptor Antagonists as a Novel Therapeutic Approach for Alzheimer’s Disease, Parkinson’s Disease, and Autism Spectrum Disorder

N‐(benzo[d]thiazol‐2‐ylcarbamothioyl)benzamide (H2L2) was synthesized as a novel thiosemicarbazide containing benzothiazole moiety, by the reaction of benzoyl isothiocyanate with 2‐aminobenzothiazole in benzene. The (H2L2) thiosemicarbazide and its isolated Cr(III), Fe(III), and Co(II) complexes were fully analyzed by different spectroscopic techniques. The thermal fragmentation of [Cr (HL2)Cl2(H2O)2].10H2O, [Co (HL2)Cl(H2O)2].6H2O, and [Fe(L2)Cl(H2O)2] were analyzed. We have also calculated the thermal parameters with using two different methods. The ligand undergoes tranamidation in the presence of PdCl2. Crystal structure of the product obtained by tranamidation is measured. Biological activities of those compounds were assessed as antioxidants, anticancer, and antimicrobial.

Synthesis of new Fe(III), Co(II), and Cr(III) complexes of N‐(benzo[d]thiazol‐2‐ylcarbamothioyl)benzamide (H2L2): Structural characterization and biological activities

/pdf/editorial-experimental-and-innovative-approaches-to-multi-1uj4wo5b.pdf

Editorial: Experimental and Innovative Approaches to Multi-Target Treatment of Parkinson's and Alzheimer's Diseases

ABSTRACTIntroduction Alzheimer’s disease is a multifactorial neurodegenerative disorder characterized by beta-amyloid accumulation and tau protein hyperphosphorylation. The disease involves interconnected mechanisms, which can be clustered into two target-packs based on the affected proteins. Pack-1 focuses on beta-amyloid accumulation, oxidative stress, and metal homeostasis dysfunction, and Pack-2 involves tau protein, calcium homeostasis, and neuroinflammation. Against this background heterocyclic system, there is a powerful source of pharmacophores to develop effective small drugs to treat multifactorial diseases like Alzheimer’s.Areas covered This review highlights the most promising heterocyclic systems as potential hit candidates with multi-target capacity for the development of new drugs targeting Alzheimer’s disease. The selection of these heterocyclic systems was based on two crucial factors: their synthetic versatility and their well-documented biological properties of therapeutic potential in neurodegenerative diseases.Expert opinion The synthesis of small drugs against Alzheimer’s disease requires a multifactorial approach that targets the key pathological proteins. In this context, the utilization of heterocyclic systems, with well-established synthetic processes and facile functionalization, becomes a crucial element in the design phases. Furthermore, the selection of hit heterocyclic should be guided by a full understanding of their biological activities. Thus, the identification of promising heterocyclic scaffolds with known biological effects increases the potential to develop effective molecules against Alzheimer’s disease.KEYWORDS: Alzheimer’s diseasebenzopyrane scaffoldbenzothiazoleheterocyclic building blocksmulti-target direct ligandpyridine scaffoldsmall drug Article highlights The design of drugs against Alzheimer’s disease (AD) should be approached from a multifactorial perspective.Heterocyclic systems provide an excellent opportunity for rapid and safe development of small multi-target drugs for Alzheimer’s disease.Heterocyclic systems with well-known, easy, and versatile synthetic pathways are fundamental in the design of small-molecule drugs.Fused heterocyclic systems, containing pyridine or pyran are privileged structures for the design of multitarget drugs.Overall, the integration of multifactorial targeting, utilization of heterocyclic systems with well-known synthesis processes, and informed selection will lead to the accelerated and efficient development of new molecules for pre-clinical evaluation against AD.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis paper was not funded. 

Advances in the discovery of heterocyclic-based drugs against Alzheimer's disease.

Abstract Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease

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Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease