Depression is identified as one of the most common psychiatric symptoms in Alzheimer's disease (AD). The comorbidity of AD and depression increases the burden of clinical treatment and care in ...elderly patients. In order to find new treatment options, we first proposed the dual RAGE/SERT inhibitors by fusing the key pharmacophore of vilazodone and azeliragon for the potential treatment of AD with comorbid depression. After a series of structural modifications, 34 dual-target directed ligands were designed and synthesized, and their RAGE and SERT inhibitory activities were systematically evaluated. Among them, compound 12 showed good dual-target bioactivities against RAGE (IC50 = 8.26 ± 1.12 μM) and SERT (IC50 = 31.09 ± 5.15 nM) in vitro, better safety profile than azeliragon, good liver microsomal stability, weak CYP inhibition, and acceptable pharmacokinetic properties. Moreover, 12 ameliorated Aβ25-35-induced neurotoxicity in SH-SY5Y cells and alleviated the depressive symptom in tail suspension test. In brief, these results indicated that 12 is a prospective prototype for the potential treatment of AD with comorbid depression.
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•A novel therapeutic strategy of RAGE/SERT inhibitors for the treatment of AD with comorbid depression was firstly proposed.•Multiple vilazodone-azeliragon chimeric derivatives were designed, synthesized and evaluated as dual RAGE/SERT inhibitors.•Compound 12 showed good RAGE/SERT inhibitory activities and better safety profile than azeliragon.•Compound 12 exhibited significant neuroprotective effect against Aβ25-35-induced neuronal damage and alleviated depressive behavior of mice.
Multi-target directed hexaflourocarbinol containing traizole amides and amines were designed by de-novo approach which can inhibit Aβ peptide aggregation by blocking the aggregation prone core, ...chelate with the excessive metals and reducing the ROS by scavenging. Novel fluorinated triazole compounds were found to inhibit Aβ aggregation, chelate biometals (Cu, Zn and Fe) and demonstrate ROS scavenging ability.
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Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer’s. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid β aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid β aggregation (IC50 of 4.6 μM) through selective binding with Amyloid β at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.
In line with the modern multi-target-directed ligand paradigm of Alzheimer’s disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated ...as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC50 of 0.271 ± 0.012 to 1.006 ± 0.075 μM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Aβ aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.
A series of benzoates (or phenylacetates or cinnamates) – tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed ...that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Aβ aggregation with an IC50 value of 51.81 nM. A Lineweaver–Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure–activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity.
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•15 novel tacrine derivatives were synthesized as multifunctional anti-AD agents.•Most of compounds showed excellent inhibition of AChE, BuChE and Aβ aggregation.•Most of compounds showed certain selectivity for AChE over BuChE.•The electron density of phenylacetate is the key to inhibitory activity of AChE.•Compound 7c was the best compound as out of the synthesized compounds.
Prion diseases are fatal neurodegenerative disorders, for which there are no effective therapeutic and diagnostic agents. The main pathological hallmark has been identified as conformational changes ...of the cellular isoform prion protein (PrP
C
) to a misfolded isoform of the prion protein (PrP
Sc
). Targeting PrP
C
and its conversion to PrP
Sc
is still the central dogma in prion drug discovery, particularly in in silico and in vitro screening endeavors, leading to the identification of many small molecules with therapeutic potential. Nonetheless, multiple pathological targets are critically involved in the intricate pathogenesis of prion diseases. In this context, multi-target-directed ligands (MTDLs) emerge as valuable therapeutic approach for their potential to effectively counteract the complex etiopathogenesis by simultaneously modulating multiple targets. In addition, diagnosis occurs late in the disease process, and consequently a successful therapeutic intervention cannot be provided. In this respect, small molecule theranostics, which combine imaging and therapeutic properties, showed tremendous potential to cure and diagnose in vivo prion diseases. Herein, we review the major advances in prion drug discovery, from anti-prion small molecules identified by means of in silico and in vitro screening approaches to two rational strategies, namely MTDLs and theranostics, that have led to the identification of novel compounds with an expanded anti-prion profile.
The development of short-peptide-based inhibitors to prevent HIV-1 entry into the host cell has been rewarded with limited success. Herein, we report a multitarget-directed ligand strategy to ...generate a series of short-peptide HIV-1 entry inhibitors that integrated the pharmacological activities of a peptide fusion inhibitor able to disrupt HIV-1 gp41 glycoprotein hexameric coiled-coil assembly and a small-molecule CCR5 antagonist that blocks the interaction between HIV-1 and its coreceptor. Among these inhibitors, dual-target 23-residue peptides SP12T and SP12L displayed dramatically increased inhibitory activities against HIV-1 replication as compared to the marketed 36-residue peptide T20. Moreover, results suggested that SP12T and SP12L successfully performed a dual-targeting mechanism. It can be concluded that these short-peptide-based HIV-1 entry inhibitors have potential for further development as candidates for a novel multitarget therapy to treat HIV-1 infection.
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•Short peptide HIV entry inhibitors were designed via a multi-target design strategy.•Chimeras were obtained by linking together a CCR5 antagonist and a short-peptide SP22.•Dual-target inhibitors showed improved anti-HIV activity than parental inhibitors.•Dual-target short peptides had dramatically increased anti-HIV potency than T20.
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•Novel multifunctional ligands were designed, synthesized and tested in vitro.•Obtained compounds presented promising anti-Alzheimer’s biological activity.•They showed affinity at H3 ...receptors and inhibition of AChE, BuChE and MAO B.•Compound 5 showed good metabolic stability and moderate hepatotoxicity.•Compound 5 is a promising candidate for further optimization.
Alzheimer’s disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common “one compound – one target” paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of 1,1ʹ-biphenyl-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of Ki values) for human histamine H3 receptors (hH3R) and good nonselective inhibitory potency (micromolar range of IC50 values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH3R/eeAChE/eqBuChE/hMAO B ligand (5: hH3R Ki = 9.2 nM; eeAChE IC50 = 2.63 µM; eqBuChE IC50 = 1.30 µM; hMAO B IC50 = 0.60 µM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, ...gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca2+-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease.
•Effect of tacrine on glutamatergic neurons is both direct and indirect.•Indirect via M1 receptor leading to inhibition of Ca2+-activated K channels.•Such inhibition prevents membrane repolarization leading to long term potentiation.•Tacrine possesses dual mechanism of action.
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•Ladostigil and ASS234 are typical propargylamine multitarget directed ligands (PMDL).•The pharmacology of some PMDL has been reviewed.•PMDL are dual inhibitors of both ...cholinesterases and monoamine oxidases.•PMDL show improvement of cognitive impairment, and antioxidant activities.•PMDL protect against tau hyperphosphorylation, regulate APP and Aβ expression.
Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aβ expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.
Alzheimer's disease (AD) is a common form of dementia affecting the elderly worldwide. It is a multifactorial neurodegenerative disorder with no known preventive therapy. Many of the drugs used in ...the treatment of AD, such as galantamine, rivastigmine, and donepezil, have unpleasant side effects, and hence physicians are keen to find alternatives. Research has shown that plants and their phytochemicals can alleviate AD. These plant products can act through various modes, such as inhibition of amyloid β, acetylcholine, and γ-secretase, modulation of antioxidants, and α-secretase activation, which are known to involve in the improvement of brain functions. A recent approach that has garnered the attention of many researchers in designing a drug against AD is the multi-target-directed ligand (MTDL), wherein the same molecule act on multiple targets. Many studies have reported the potential of herbs to act on multiple targets and display biological properties. The current review summarizes the ongoing evidence on the use of herbs and their derived bioactive molecules in the treatment of AD and in relieving disease-associated pathological events. Currently available plant-derived MTDLs for the treatment or slowing down of the progression of AD are also discussed.
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