Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity

Jismy, Badr; Qami, Abdelkarim El; Pišlar, Anja; Frlan, Rok; Kos, Janko; Gobec, Stanislav; Knez, Damijan; Abarbri, Mohamed

doi:10.1016/j.ejmech.2020.112911

Cited by 29 publications

(21 citation statements)

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“…Accordingly, only compounds 3n and 3r were further investigated for their neuroprotective effects against oxidative toxicity induced by 6-OHDA or rotenone in PC12 cells. [106][107][108]. 6-OHDA induces dopaminergic neurotoxicity after cellular uptake by producing ROS, which contributes to cell death.…”

Section: Molecular Docking Study Over Mao-amentioning

confidence: 99%

“…3.5.2. Neuroprotective Effects of Compounds 3n and 3r on 6-OHDA-Induced Oxidative Toxicity in PC12 Cells 6-OHDA-induced PC12 cells are widely used as a model of PD to evaluate the neuroprotective potential of compounds in the early stages of preclinical drug development[106][107][108]. 6-OHDA induces dopaminergic neurotoxicity after cellular uptake by producing ROS, which contributes to cell death.…”

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confidence: 99%

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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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Section: Molecular Docking Study Over Mao-amentioning

confidence: 99%

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confidence: 99%

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

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“…4 Very recently, Jismy et al investigated the treatment of 3-amino-1H-indazoles with 2bromomalonaldehyde in ethanol in the presence of catalytic acetic acid which afforded the products in high yields (Scheme 1c). 2 With growing interest in this area, the present work reports for the rst time a new series of pyrimido [1,2-b]indazoles featuring indolenine scaffolds. The compounds were prepared via a simple condensation reaction between the substituted diformyl indolenines and 3-amino-1H-indazoles catalysed by acetic acid.…”

Section: Introductionmentioning

confidence: 99%

Indoleninyl-substituted pyrimido[1,2-b]indazoles via a facile condensation reaction

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“…as base in dioxane/H 2 O (4/1) at 90°C (Table 1, entry 1). [29] The analysis of the crude 1 H-NMR spectrum showed the formation of a complex mixture. Replacing PdCl 2 (PPh 3 ) 2 by the Pd(OAc) 2 (5 mol %)/PPh 3 (10 mol %) tandem in a mixture of DME/EtOH/ H 2 O (3/1/1) at 65°C under microwave irradiation did not improve the result (Table 4, entry 2).…”

Section: C4-suzuki-miyaura Coupling Reactionmentioning

confidence: 99%

Efficient Synthesis of tert‐Butyl 2,4‐Dialkynylated and 2‐Alkynylated‐4‐Arylated‐1H‐Imidazole‐1‐Carboxylate via Regioselective Sonogashira Cross‐Coupling Reaction

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Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity

Cited by 29 publications

References 54 publications

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

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

Indoleninyl-substituted pyrimido[1,2-b]indazoles via a facile condensation reaction

Efficient Synthesis of tert‐Butyl 2,4‐Dialkynylated and 2‐Alkynylated‐4‐Arylated‐1H‐Imidazole‐1‐Carboxylate via Regioselective Sonogashira Cross‐Coupling Reaction

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