Discovery of novel indole-based aroylhydrazones as anticonvulsants: Pharmacophore-based design

Angelova, Violina T.; Rangelov, Miroslav; Todorova, Nadezhda; Dangalov, Miroslav; Andreeva-Gateva, Pavlina; Kondeva-Burdina, Magdalena; Karabeliov, Valentin; Shivachev, Boris; Tchekalarova, Jana

doi:10.1016/j.bioorg.2019.103028

Cited by 33 publications

(12 citation statements)

References 25 publications

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“…IR spectra were recorded using potassium bromide disks on a Spectrum One FT-IR spectrophotometer (Perkin Elmer, Milan, Italy); only the most significant IR absorption bands are reported. 1 [19], 30 [45], 33 [15], 44 [23] and 45 [24] have been prepared according to quoted references and their analytical data agreed with those reported in the literature.…”

Section: General Informationmentioning

confidence: 94%

“…Finally, the synthesis of the indolinone 43 was carried out under neat conditions starting from indoxyl acetate and dihydroxyquinolinedione 42 [22] (Scheme 9). Compounds 44 [23] and 45 [24] were prepared according to the quoted references. [22] (Scheme 9).…”

Section: Chemistrymentioning

confidence: 99%

“…For some representative compounds, HRMS experiments were performed with a dual electrospray interface (ESI) and a quadrupole time-of-flight mass spectrometer (Q-TOF, Agilent 6530 Series Accurate-Mass Quadrupole Time-of-Flight LC/MS, Agilent Technologies Italia S.p.A., Cernusco sul Naviglio, Italy). Compounds 2 [42], 4 [43], 5 [44], 10-12 and 14 [19], 30 [45], 33 [15], 44 [23] and 45 [24] have been prepared according to quoted references and their analytical data agreed with those reported in the literature. Specifically, panels (a,c,e) show the most active ligands within hydrophobic, HBD and electron withdrawing region, respectively; panels (b,d,f) show the most inactive ligands within hydrophobic, HBD and electron withdrawing regions, respectively.…”

Section: General Informationmentioning

confidence: 99%

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Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

et al. 2020

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Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aβ) aggregation, a hallmark of pathophysiology of Alzheimer’s disease. The newly synthesized molecules spanned their IC50 values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the ‘active’ compounds from the ‘inactive’ (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of ‘active’ compounds, i.e., those achieving finite IC50 values lower than 100 μM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q2 = 0.596) and in the external test set (n = 14, r2ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aβ anti-aggregating potency of the indole and isatin derivatives studied herein.

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Section: General Informationmentioning

confidence: 94%

Section: Chemistrymentioning

confidence: 99%

Section: General Informationmentioning

confidence: 99%

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Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

et al. 2020

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“…[59][60][61]. Accordingly, different research groups have reported several synthetic derivatives of melatonin as potential modulators to different human disorders including neurodegenerative diseases [62][63][64][65][66][67][68][69]. Several studies have indicated that the potent ability of melatonin to scavenge ROS including 1 O2, O2 •− , H2O2, hydroxyl radical (HO • ), and ROO • , is mainly due to the presence of the electron-rich aromatic indole ring system (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress

et al. 2021

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Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson’s disease (PD). Herein, 24 melatonin analogues (3a–x) were synthesized as novel MAO-B inhibitors with the potential to counteract oxidative stress in neuronal PC12 cells. Structure elucidation, characterization, and purity of the synthesized compounds were performed using 1H-NMR, 13C-NMR, HRMS, and HPLC. At 10 µM, 12 compounds showed >50% MAO-B inhibition. Among them, compounds 3n, 3r, and 3u‒w showed >70% inhibition of MAO-B and IC50 values of 1.41, 0.91, 1.20, 0.66, and 2.41 µM, respectively. When compared with the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), compounds 3n, 3r, 3u, and 3v demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively). Furthermore, compounds 3n and 3r exhibited safe neurotoxicity profiles in PC12 cells and reversed 6-OHDA- and rotenone-induced neuronal oxidative stress. Both compounds significantly up-regulated the expression of the anti-oxidant enzyme, heme oxygenase (HO)-1. Treatment with Zn(II)-protoporphyrin IX (ZnPP), a selective HO-1 inhibitor, abolished the neuroprotective effects of the tested compounds, suggesting a critical role of HO-1 up-regulation. Both compounds increased the nuclear translocation of Nrf2, which is a key regulator of the antioxidative response. Taken together, these data show that compounds 3n and 3r could be further exploited for their multi-targeted role in oxidative stress-related PD therapy.

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“…The anticonvulsant action of melatonin is mediated via specific melatonin receptors that control seizure threshold ( 89 , 90 ). Further, the melatonin receptor agonist ramelteon possesses anticonvulsant effects and newer melatonin receptor drugs are under development ( 91 – 93 ). Clinical studies show that melatonin rhythm is normal in patients with epilepsy, but compared to control individuals, melatonin levels are low ( 94 , 95 ).…”

Section: Core Clock Mechanisms Influence Neuronal Excitabilitymentioning

confidence: 99%

The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy

Batterman

Gerstner

et al. 2020

Front. Neurol.

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Seizure patterns observed in patients with epilepsy suggest that circadian rhythms and sleep/wake mechanisms play some role in the disease. This review addresses key topics in the relationship between circadian rhythms and seizures in epilepsy. We present basic information on circadian biology, but focus on research studying the influence of both the time of day and the sleep/wake cycle as independent but related factors on the expression of seizures in epilepsy. We review studies investigating how seizures and epilepsy disrupt expression of core clock genes, and how disruption of clock mechanisms impacts seizures and the development of epilepsy. We focus on the overlap between mechanisms of circadian-associated changes in SCN neuronal excitability and mechanisms of epileptogenesis as a means of identifying key pathways and molecules that could represent new targets or strategies for epilepsy therapy. Finally, we review the concept of chronotherapy and provide a perspective regarding its application to patients with epilepsy based on their individual characteristics (i.e., being a "morning person" or a "night owl"). We conclude that better understanding of the relationship between circadian rhythms, neuronal excitability, and seizures will allow both the identification of new therapeutic targets for treating epilepsy as well as more effective treatment regimens using currently available pharmacological and non-pharmacological strategies.

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Discovery of novel indole-based aroylhydrazones as anticonvulsants: Pharmacophore-based design

Cited by 33 publications

References 25 publications

Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress

The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy

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