Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents

Patel, Dushyant V.; Patel, N. K.; Kanhed, Ashish M.; Teli, Divya M.; Patel, Kishan B; Joshi, Prashant D.; Patel, Sagar P.; Gandhi, Pallav M.; Chaudhary, Bharat N; Prajapati, Navnit; Patel, Kirti; Yadav, Mange Ram

doi:10.1016/j.bioorg.2020.103977

Cited by 30 publications

(23 citation statements)

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“…AChE-docked 4-aminopyridine semicarbazone derivatives with biphenyl rings had stronger hydrophobic interactions and overall better binding affinities than derivatives without those groups [ 199 ]. Carbazole-based stilbene derivatives were also docked with both cholinesterases, as well as the Aβ 1-42 peptide, and displayed potential as a multitarget inhibitor for AD in a 2020 study by Patel et al [ 200 ].…”

Section: Inhibitionmentioning

confidence: 99%

A Comprehensive Review of Cholinesterase Modeling and Simulation

et al. 2021

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The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The inhibitory activities of myriad compounds have been computationally assessed, primarily through Monte Carlo-based docking calculations and molecular dynamics simulations. Pharmaceutical compounds examined herein include FDA-approved therapeutics and their derivatives, as well as several other prescription drug derivatives. Cholinesterase interactions with both narcotics and organophosphate compounds are discussed, with the latter focusing primarily on molecular recognition studies of potential therapeutic value and on improving our understanding of the reactivation of cholinesterases that are bound to toxins. This review also explores the inhibitory properties of several other organic and biological moieties, as well as advancements in virtual screening methodologies with respect to these enzymes.

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Section: Inhibitionmentioning

confidence: 99%

A Comprehensive Review of Cholinesterase Modeling and Simulation

et al. 2021

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“…The ability of the substituted triazinoindoles to inhibit self-mediated Aβ 1−42 aggregation was assessed using the Thioflavin T (ThT)-based fluorescence assay as detailed in our earlier report. 52 Curcumin was used as a reference compound.…”

Section: Chemistry 521 Synthesis Of Substituted Isatinsmentioning

confidence: 99%

“…The ability of the synthesized compounds to inhibit ChEs was evaluated using Ellman’s method as presented in our earlier reports. ,, Tacrine and donepezil were used as standard compounds.…”

Section: Experimental Sectionmentioning

confidence: 99%

“…5.2.5b. 6,8-Dichloro-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine(52). The title compound (52) was synthesized from sulfone (42, 0.5 g, 1.58 mmol) and 6-(pyrrolidin-1yl)hexan-1-amine (2.69 g, 15.8 mmol) as per Method D. Yellow solid (yield: 0.44 g, 68%); mp >250 °C; IR (KBr, cm −1 ): 3405, 3062, 2931, 1608, 1528, 1376, 1312, 1076, 834, 724; 1 H NMR (DMSO-d 6 ): δ 7.43 (d, J = 2.1 Hz, 1H, ArH), 7.39 (d, J = 2.1 Hz, 1H, ArH), 3.35− 3.45 (m, 2H, −NHCH 2 ), 2.36−2.51 (m, 6H, −NCH 2 ), 1.56−1.71 (m, 6H, −NCH 2 CH 2 ), 1.42−1.49 (m, 2H, −NHCH 2 CH 2 ), 1.31− 1.40 (m, 4H, −CH 2 ); MS (m/z): 407.31 [M] + , 409.25 [M + 2] + ; RP-HPLC: purity = 97.6%, t R = 6.88 min.…”

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confidence: 99%

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Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents

Patel

Kanhed

et al. 2020

ACS Chem. Neurosci.

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The inadequate clinical efficacy of the present anti-Alzheimer’s disease (AD) drugs and their low impact on the progression of Alzheimer’s disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 μM; BuChE, IC50 value of 0.21 μM), was also found to possess significant self-mediated Aβ1–42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ1–42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.

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“…This age-related neurodegenerative disease is characterized by progressive and irreversible cognitive deterioration, loss of memory, and behavioral disturbances. Individuals suffering from this neurodegenerative disorder, on the other hand, require constant human and medical care, which create a heavy socio-economic burden on the health care system [ 2 ]. Continued research on AD has revealed that low levels of acetylcholine, formation of β-amyloid (Aβ) deposits, oxidative stress, metal imbalance, inflammation, and immune suppression are involved in the pathogenesis and progression of AD [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Enzymatic and Kinetic Studies, and In Silico Drug-Receptor Interactions, and Drug-Like Profiling of the 5-Styrylbenzamide Derivatives as Potential Cholinesterase and β-Secretase Inhibitors with Antioxidant Properties

Mphahlele

Agbo

et al. 2021

Antioxidants

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The 5-(styryl)anthranilamides were transformed into the corresponding 5-styryl-2-(p-tolylsulfonamido)benzamide derivatives. These 5-styrylbenzamide derivatives were evaluated through enzymatic assays in vitro for their capability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) activities as well as for antioxidant potential. An in vitro cell-based antioxidant activity assay involving lipopolysaccharides (LPS)-induced reactive oxygen species (ROS) production revealed that compounds 2a and 3b have the capability of scavenging free radicals. The potential of the most active compound, 5-styrylbenzamide (2a), to bind copper (II) or zinc (II) ions has also been evaluated spectrophotometrically. Kinetic studies of the most active derivatives from each series against the AChE, BChE, and β-secretase activities have been performed. The experimental results are complemented with molecular docking studies into the active sites of these enzymes to predict the hypothetical protein–ligand binding modes. Their drug likeness properties have also been predicted.

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Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents

Cited by 30 publications

References 50 publications

A Comprehensive Review of Cholinesterase Modeling and Simulation

A Comprehensive Review of Cholinesterase Modeling and Simulation

Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents

In Vitro Enzymatic and Kinetic Studies, and In Silico Drug-Receptor Interactions, and Drug-Like Profiling of the 5-Styrylbenzamide Derivatives as Potential Cholinesterase and β-Secretase Inhibitors with Antioxidant Properties

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