Design, synthesis, biological evaluation and molecular modelling of 2-(2-aryloxyphenyl)-1,4-dihydroisoquinolin-3(2H)-ones_ A novel class of TSPO ligands modulating amyloid-β-induced mPTP opening (original) (raw)
Related papers
Herein, we report a new series of aliphatic substituted pyridyl-urea small molecules synthesized as potential modulators for amyloid beta (Ab) induced mitochondrial dysfunction. Their blocking activities against Ab-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (DJm). The inhibitory activity of sixteen compounds against Ab-induced mPTP opening was superior or almost similar to that of the standard Cyclosporin A (CsA). Among them, 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl) urea (5x) effectively maintained mitochondrial function and cell viabilities on ATP assay, MTT assay, and ROS assay. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for 5x with cyclophilin D (CypD) receptor as a major component of mPTP. Moreover, hERG and BBB-PAMPA assays presented safe cardiotoxicity and high CNS bioavailability profiles for 5x. Taken as a whole, this report presents compound 5x as a new nonpeptidyl mPTP blocker may hold a promise for further development of Alzheimer's disease (AD) therapeutics.
A novel series of twenty-six quinazoline-urea derivatives was designed and synthesized. Their blocking activities against b-amyloid peptide (Ab) induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measured the change of mitochondrial membrane potential. Seven compounds showed better inhibitory activities than the standard Cyclosporin A (CsA). The most active analogues were tested by MTT assay to evaluate their toxicity on the cellular survival; they revealed excellent cellular viability. To explain the difference in inhibitory activity, molecular docking study using (GOLD) program was performed for selected sets of the most active and inactive compounds on cyclophilin D (CypD) receptor as a major component of mPTP. Moreover, ADME profiling, in silico toxicity, drug-likeness, and drug-score studies were discussed. From these results, we report compound 31 as the most active nonpeptidyl mPTP blocker possessing quinazoline-urea scaffold; 2 folds of CsA activity, which would constitute a new direction for the design of novel mPTP modulators.
International Journal of Molecular Sciences, 2019
Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase’s inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound....
Journal of Medicinal Chemistry, 2014
Structure−activity relationships (SARs) within the 4-phenylquinazoline-2-carboxamide series of translocator protein (TSPO) ligands have been explored further by the synthesis and TSPO binding affinity evaluation of N-benzyl-N-ethyl/methyl derivatives variously decorated at the 6-, 2′-, 4′-, and 4″-positions. Most of the compounds showed high affinity with K i values in the nanomolar/subnanomolar range. A pharmacophore model was developed and employed to better address SAR data presented by the new TSPO ligands. A subset of the new compounds (5, 8, 12, and 19) were tested for their ability to inhibit the viability of human glioblastoma cell line U343. The observed antiproliferative effect was demonstrated to be specific for compound 19, endowed with the best combination of binding affinity and efficacy. Furthermore, the ability of 19 to induce mitochondrial membrane dissipation (Δψ m) substantiated the intracellular pro-apoptotic mechanism activated by the binding of this class of ligands to TSPO.
ChemMedChem, 2015
The mitochondrial permeability transition pore (mtPTP) is a Ca 2+-requiring mega-channel which, under pathological conditions, leads to the deregulated release of Ca 2+ and mitochondrial dysfunction, ultimately resulting in cell death. Although the mtPTP is a potential therapeutic target for many human pathologies, its potential as a drug target is currently unrealized. Herein we describe an optimization effort initiated around hit 1, 5-(3-hydroxyphenyl)-N-(3,4,5trimethoxyphenyl)isoxazole-3-carboxamide, which was found to possess promising inhibitory activity against mitochondrial swelling (EC 50 < 0.39 µM) and showed no interference on the inner mitochondrial membrane potential (rhodamine 123 uptake EC 50 > 100 µM). This enabled the construction of a series of picomolar mtPTP inhibitors that also potently increase the calcium retention capacity of the mitochondria. Finally, the therapeutic potential and in vivo efficacy of one of the most potent analogues, N-(3-chloro-2-methylphenyl)-5-(4-fluoro-3hydroxyphenyl)isoxazole-3-carboxamide (60), was validated in a biologically relevant zebrafish model of collagen VI congenital muscular dystrophies.
ACS Chemical Neuroscience, 2019
Protein misfolding and amyloid formation are associated with various human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Type-2 Diabetes mellitus (T2DM). No disease-modifying therapeutics are available for them. Despite the lack of sequence homology between the corresponding proteins, aromatic residues are recognized as common key motifs in the formation and stabilization of amyloid structures via π-π stacking. Thus, targeting aromatic recognition interfaces could be a useful approach for inhibiting amyloid formation as well as disrupting the pre-formed amyloid fibrils. Combining experimental and computational approaches, we demonstrated the anti-amyloidogenic effect of Tryptophan-Naphthoquinone-based hybrid molecules towards PHF6 (tau-derived aggregative peptide), Amyloid β (Aβ42), and human islet amyloid polypeptide (hIAPP) implicated in AD and T2DM, respectively. These hybrid molecules significantly inhibited the aggregation and disrupted their pre-formed fibrillar aggregates in vitro, in a dose-dependent manner as evident from Thioflavin T/S binding assay, CD spectroscopy, and Electron microscopy. Dye leakage assay from LUVs and cell-based experiments indicated that the hybrid molecules inhibit membrane disruption and cytotoxicity induced by these amyloids. Furthermore, in silico studies provided probable mechanistic insights into the interaction of these molecules with the amyloidogenic proteins in their monomeric or aggregated forms, including the role of hydrophobic interaction, hydrogen bond formation, and packing during inhibition of aggregation and fibril disassembly. Our findings may help in designing novel therapeutics towards AD, T2DM and other proteinopathies based on the Naphthoquinone derived hybrid molecules.
Bioorganic & Medicinal Chemistry, 2016
Diseases of the CNS are often complex and involve multiple receptor systems and thus, the treatment options for these diseases must focus on targeting the multiple receptors implicated in the various disorders. Schizophrenia and depression are examples of such diseases and their pharmacotherapy thus depends on agents which target multiple receptors including the dopamine, serotonin and even cholinergic receptors at the same time. In our previous campaign to find multireceptor ligands, we have identified the benzothiazole 1a as an initial lead molecule. In the current work, we have expanded the structure affinity relationship (SAFIR) of 1a resulting in the identification of a partially restrained butyrophenone 3j as a potent and selective dual 5-HT 1A and 5-HT 7 receptor ligand. It is expected that compound 3j may serve as a new lead for further development in our search for newer and novel ligands with the potential to treat diseases of CNS origin.
A series of 2-(3-arylureido)pyridines and 2-(3-benzylureido)pyridines were synthesized and evaluated as potential modulators for amyloid beta (Ab)-induced mitochondrial dysfunction in Alzheimer's disease (AD). The blocking activities of forty one small molecules against Ab-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mito-chondrial membrane potential (DJm). The inhibitory activity of twenty five compounds against Ab-induced mPTP opening was superior to that of the standard cyclosporin A (CsA). Six hit compounds have been identified as likely safe in regards to mitochondrial and cellular safety and subjected to assessment for their protective effect against Ab-induced deterioration of ATP production and cytotoxicity. Among them, compound 7fb has been identified as a lead compound protecting neuronal cells against 67% of neurocytotoxicity and 43% of suppression of mitochondrial ATP production induced by 5 mM concentrations of Ab. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for these compounds with cyclophilin D (CypD) receptor as a major component of mPTP. Hence, this report presents compound 7fb as a new nonpeptidyl mPTP blocker which would be promising for further development of Alzheimer's disease (AD) therapeutics.
Alzheimer's disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of b-amyloid (Ab), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC 50 value of 0.052 mM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC 50 values from 0.071 to 0.797 mM. Compound 3b exhibited strong Ab 1-42 aggregation inhibitory effect with 25.7% at 5 mM to 92.8% at 100 mM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment.