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Neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's diseases have multifaceted nature because of the different factors contributing to their progression. The complex nature of neurodegenerative diseases has developed a pressing need to design multitarget-directed ligands to address the complementary pathways involved in these diseases. The major enzyme targets for development of therapeutics for Alzheimer's disease are cholinesterase and β-secretase enzymes. In this review, we discuss recent advances in profiling single target inhibitors based on these enzymes to multitarget-directed ligands as potential therapeutics for this devastating disease. In addition, therapeutics based on iron chelation strategy are discussed as well.

With the global surge of infections caused by multidrug‐resistant (MDR) Gram‐negative bacteria, there is an urgent need for breakthrough therapeutic approaches. To overcome the intrinsic resistance mechanisms of bacteria, End‐alkyl‐modified dipiperazine‐phenyl derivatives are designed via convergent molecular platforms (CMPs)‐guided multi‐target directed ligand (MTDL) strategy. These dual‐functional compounds not only inhibit the AcrB‐TolC efflux pump system but also enhance bacterial membrane permeability and display a distinctive activity profile across a broad concentration range. Through integrated evaluation combining in vitro activity screening and computational ADMET (absorption, distribution, metabolism, excretion, toxicity) profiling, compound C5 is identified as a promising lead candidate. This compound achieved three notable breakthroughs. First, it reduces biofilm formation by 80% at 1/64 minimum inhibitory concentration (MIC) when combined with antibiotics. Second, unlike conventional antibiotic adjuvants that typically display potentiation within a narrow concentration window (1/4 MIC), C5 maintained robust and consistent synergistic activity across a broad range from 1/64 MIC to 1/4 MIC. Third, C5 markedly enhanced the therapeutic efficacy of antibiotics such as minocycline by over 1000‐fold in in vivo infection models, without causing detectable acute toxicity or cytotoxicity. The established MTDL‐CMPs integrated platform pioneers a novel “pump‐membrane dual blockade” therapeutic paradigm against MDR Enterobacteriaceae infections.

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

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 H 3 receptor ligands (H 3 R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a K i value of 0.012 μM. The multitargeting potential of these H 3 R 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 K i value of 0.036 μM at H 3 R and IC 50 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 multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

About twenty molecules sharing 1H-chromeno[3,2-c]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1H-indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2-c]pyridin-10-ones (1,2,3,4-THCP-10-ones, 1) or 2,3-dihydro-2-methyl-1H-chromeno[3,2-c]pyridines (2,3-DHPCs, 2). The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives 2 inhibit MAO A (IC50 about 1 μM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a, bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC50 0.51 μM) and moderate inhibitor of both ChEs (IC50s 7–8 μM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC50 of 3.51 μM. The MAO B inhibitor 3a deserves further pharmacological studies as a remedy in the symptomatic treatment of Parkinson’s disease and neuroprotectant for Alzheimer’s disease. Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported. Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog 6c exerts anti-tumor activity with IC50s in the range 4.83–11.3 μM.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, cognitive impairment, and functional decline leading to dementia and death. AD imposes neuronal death by the intricate interplay of different neurochemical factors, which continue to inspire the medicinal chemist as molecular targets for the development of new agents for the treatment of AD with diverse mechanisms of action, but also depict a more complex AD scenario. Within the wide variety of reported molecules, this review summarizes and offers a global overview of recent advancements on naphthoquinone (NQ) and anthraquinone (AQ) derivatives whose more relevant chemical features and structure-activity relationship studies will be discussed with a view to providing the perspective for the design of viable drugs for the treatment of AD. In particular, cholinesterases (ChEs), β-amyloid (Aβ) and tau proteins have been identified as key targets of these classes of compounds, where the NQ or AQ scaffold may contribute to the biological effect against AD as main unit or significant substructure. The multitarget directed ligand (MTDL) strategy will be described, as a chance for these molecules to exhibit significant potential on the road to therapeutics for AD.

Alzheimer’s disease (AD) is multifactorial, progressive and the most predominant cause of cognitive impairment and dementia worldwide. The current “one-drug, one-target” approach provides only symptomatic relief to the condition but is unable to cure the disease completely. The conventional single-target therapeutic approach might not always induce the desired effect due to the multifactorial nature of AD. Hence, multitarget strategies have been proposed to simultaneously knock out multiple targets involved in the development of AD. Herein, we provide an overview of the various strategies, followed by the multitarget-directed ligand (MTDL) development, rationale designs and efficient examples. Furthermore, the effects of the linkers and substitutional functional groups on MTDLs against various targets of AD and their modes of action are also discussed.

Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In this context, recent studies have shown that simultaneous inhibition of PI3K and histone deacetylases (HDAC) promotes synergistic antitumor effects in different cancer cell lines. HDACs are validated epigenetic targets that are extensively explored in clinical practice and have a pharmacophore with versatility for structural modifications, which facilitates the design of multitarget inhibitors. This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the development of fimepinostat, the first clinically evaluated agent exhibiting potent and balanced inhibition of both targets. We provide a critical overview of PI3K/HDAC multitarget inhibitors reported in recent years that have progressed to preclinical or clinical investigation, discussing the structural frameworks employed, medicinal chemistry strategies adopted, and structure–activity relationships established. Particular attention is given to advantageous molecular features as well as challenges related to toxicity, pharmacokinetic behavior, and pharmacodynamic modulation. From this comprehensive analysis, we outline key considerations and emerging design principles that may inform the next generation of PI3K/HDAC multitarget drug candidates. Insights derived from the diversity of chemical scaffolds, activity profiles, and selectivity patterns described herein may support the development of innovative therapeutic agents capable of overcoming current limitations in anticancer treatment.