Aug 2026· Zeitschrift für Naturforschung C - A Journal of Biosciences· 0 citations· 118 references
Medicine
TL;DR
Recent advances in multitarget drug development for AD and PD targeting compounds targeting Aβ, BACE1, MAO-B, cholinesterases, metal-ion dyshomeostasis, oxidative stress, and inflammatory pathways are reviewed.
Abstract
Abstract Neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are multifactorial diseases that are characterized by several interconnected pathological mechanisms, such as the aggregation of amyloid-beta (Aβ), hyperphosphorylation of tau, accumulation of α-synuclein, oxidative stress, mitochondrial dysfunction, neuroinflammation, and neurotransmitter imbalance. Conventional single-target therapies failed to produce significant clinical effects due to the fact that they target only individual disease pathways. Thus, the multitarget-directed ligand (MTDL) strategy has become an attractive therapeutic option, and MTDLs can act on several pathological targets simultaneously. Recent advances in multitarget drug development for AD and PD targeting compounds targeting Aβ, BACE1, MAO-B, cholinesterases, metal-ion dyshomeostasis, oxidative stress, and inflammatory pathways are reviewed. A few potential candidates, such as GV-971, Prasinezumab, Huperzine A, curcumin derivatives, and hybrids of MAO-B inhibitors, have shown neuroprotective and cognitive effects in preclinical and clinical studies. There are significant advances in the clinical pipeline, with over 180 clinical trials for AD and over 130 clinical trials for PD testing multitarget or disease-modifying strategies. The review also highlights the growing importance of computer-aided drug design (CADD), artificial intelligence (AI), and machine learning (ML) in speeding up the discovery of MTDL, optimizing their pharmacokinetic profiles, and predicting multitarget interactions. However, there are still major obstacles to be overcome, such as the ability to cross the blood–brain barrier, optimizing the pharmacokinetics, the difficulties of transferring from the animal to the human model, and the complexity of the regulatory process. New strategies based on nanomedicine, biomarker-driven trials, personalized medicine, and drug repurposing will enhance therapeutic precision and clinical success.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory loss, resulting from various pathological processes such as amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, cholinergic dysfunction, and metal ion imbalance. Current treatments, like acetylcholinesterase inhibitors and NMDA receptor antagonists, only help with the symptoms and don't change how the disease gets worse. The fact that AD has many causes shows how important it is to come up with new ways to treat it. Multi-target directed ligands (MTDLs) have become a promising approach in the last few years. They are meant to work on several important molecular targets that are thought to play a role in the development of Alzheimer's disease. This review summarises progress in the creation and design of MTDLs. It talks about hybrid molecules (like tacrine–chromene derivatives), peptide-based scaffolds, flavonoid conjugates, dual GSK-3β/tau aggregation inhibitors, and new PDE- and AChE-targeting compounds. Compared to regular polypharmacy, MTDLs have more benefits, such as better effectiveness, less toxicity, better compliance, and better pharmacological profiles. Recent advances in medicinal chemistry and structure-based design bolster the argument for MTDLs as next-generation therapeutic candidates, notwithstanding challenges like bioavailability and blood–brain barrier penetration. Ongoing enhancement of these compounds may eventually yield disease-modifying therapies that can impede or avert the advancement of Alzheimer's disease.
Sumesh Kumar, Vansh Sharma, Happy et al.· Current Pharmaceutical Resea...· 0 citations
A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.
Nagaraj Rangappa, Riddhi Upadhyay, Nathish Lakshman et al.· Advances in Protein Chemistr...· 0 citations
A progressive neurodegenerative disease, Alzheimer's Disease (AD), is typified by cognitive decline, synaptic malfunction, and permanent death of neurons. It has a complicated etiology that includes oxidative stress, neuroinflammatory cascades, and monoamine oxidase dysregulation; therapies are limited in their long-term efficacy. This highlights the necessity for carefully crafted multi-target medicines that can modulate multiple pathogenic pathways at once. The advantageous electronic characteristics and structural flexibility of thiazole and benzothiazole derivatives make them appealing, as they can penetrate the blood-brain barrier and serve as heterocyclic scaffolds in medicinal chemistry. According to recent studies, thiazole-based drugs have a strong inhibitory effect against butyrylcholinesterase and acetylcholinesterase, increasing the availability of acetylcholine in synapses. Monoamine oxidase-B (MAO-B) is also strongly and selectively inhibited by several derivatives, which helps to lower oxidative stress and promote neuroprotection. Significantly affecting enzyme affinity, selectivity, and multitarget engagement are structural alterations such as halogen substitution, methoxy incorporation, hydrazone connections, and sulfonamide or piperazine moieties. Beyond enzyme modulation, thiazole-containing molecules interfere with Aβ aggregation, disrupt β-sheet fibril formation, and demonstrate antioxidant and metal-chelating properties. These combined biological effects position thiazole derivatives as potentially disease-modifying multitarget- directed ligands. According to an analysis of the evaluated research, the most effective anti- Alzheimer effects were found in thiazole and benzothiazole derivatives with halogen, methoxy, hydrazone, piperazine, and sulfonamide substituents. Many substances showed nanomolar to low micromolar inhibition of AChE, BuChE, and MAO-B while concurrently inhibiting oxidative stress and amyloid-β formation. Studies on the structure-activity link have shown how crucial strategic substitution patterns are for improving potency, selectivity, and multitarget engagement. This research highlights the feasibility of using thiazoles as scaffold pharmacophores for developing novel drugs to treat Alzheimer's disease and provides vital guidance on the development of future drugs. This review is a comprehensive compilation of small thiazoles being studied for AD with emphasis on structure-activity relationships, molecular targets, and multitarget therapies. This review provides useful information for the rational design of next-generation anti-Alzheimer drugs. It highlights prospective directions for future drug discovery research by methodically outlining current achievements in thiazole-derived AChE, BuChE, MAO-B, and amyloid-β inhibitors.
Geetanjali Chaudhary, Deepika Paliwal, Aman Thakur et al.· Mini-Reviews in Medical Chem...· 0 citations
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.
Sana Saffour, Turgut Seckin Gul, H. Gul· Future Medicinal Chemistry· 0 citations
New knowledge about the protective and detrimental aspects of neuroinflammation in AD and PD is summarized, providing an analysis on these developing prospects for targeted interventions toward slowing or stopping neurodegeneration.
R. Kumar, Kamaljeet, Sourabh Kosey· InflammoPharmacology· 0 citations
Natural bioactive compounds, gene-based therapies, stem cell-based therapies, stem cell-based therapies, and nanotechnology-assisted drug delivery systems are promising alternatives as suggested by recent advances and could help to more effectively and permanently manage PD.
S. Arbab, Hanif Ullah, Yanting Han et al.· Ageing Research Reviews· 0 citations
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