Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction

Elkamhawy, Ahmed; Park, Jung-eun; Hassan, Ahmed H.E.; Ra, Hyunhwa; Pae, Ae Nim; Lee, Jiyoun; Park, Beoung-Geon; Moon, Bongjin; Park, Hyun‐Mee; Roh, Eun Joo

doi:10.1016/j.ejmech.2016.12.057

Cited by 29 publications

(24 citation statements)

References 46 publications

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“…The indole scaffold is considered one of the most privileged heterocyclic motifs among those attracting the attention of medicinal chemists and has become a center of research due to its unique pharmacological properties, with anticancer, anti-inflammatory, and antimicrobial applications [13][14][15]. As a continuation of our efforts to develop new small molecules as potential candidates for neurodegenerative disorders [16,17], we recently generated new indole-based MAO-B inhibitory leads [18] from previously reported indazole derivatives (IV, V, and VI, Figure 2) [19]. In our previous study, the The indole scaffold is considered one of the most privileged heterocyclic motifs among those attracting the attention of medicinal chemists and has become a center of research due to its unique pharmacological properties, with anticancer, anti-inflammatory, and antimicrobial applications [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress

et al. 2021

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Monoamine oxidase B (MAO-B) is responsible for dopamine metabolism and plays a key role in oxidative stress by changing the redox state of neuronal and glial cells. To date, no disease-modifying therapy for Parkinson’s disease (PD) has been identified. However, MAO-B inhibitors have emerged as a viable therapeutic strategy for PD patients. Herein, a novel series of indole-based small molecules was synthesized as new MAO-B inhibitors with the potential to counteract the induced oxidative stress in PC12 cells. At a single dose concentration of 10 µM, 10 compounds out of 30 were able to inhibit MAO-B with more than 50%. Among them, compounds 7b, 8a, 8b, and 8e showed 84.1, 99.3, 99.4, and 89.6% inhibition over MAO-B and IC50 values of 0.33, 0.02, 0.03, and 0.45 µM, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), compounds 7b, 8a, 8b and 8e showed remarkable selectivity indices (SI > 305, 3649, 3278, and 220, respectively). A further kinetic study displayed a competitive mode of action for 8a and 8b over MAO-B with Ki values of 10.34 and 6.63 nM. Molecular docking studies of the enzyme-inhibitor binding complexes in MAO-B revealed that free NH and substituted indole derivatives share a common favorable binding mode: H-bonding with a crucial water “anchor” and Tyr326. Whereas in MAO-A the compounds failed to form favorable interactions, which explained their high selectivity. In addition, compounds 7b, 8a, 8b, and 8e exhibited safe neurotoxicity profiles in PC12 cells and partially reversed 6-hydroxydopamine- and rotenone-induced cell death. Accordingly, we report compounds 7b, 8a, 8b, and 8e as novel promising leads that could be further exploited for their multi-targeted role in the development of a new oxidative stress-related PD therapy.

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Section: Introductionmentioning

confidence: 99%

Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress

et al. 2021

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“…In light of its importance, we checked the permeability of compound 6e across the GIT membrane employing in vitro Parallel artificial membrane permeability assay (PAMPA). The PAMPA assay might be used to simulate passive diffusion across biological barriers such as membranes of GIT and BBB 49 . Simply, the compound of interest is located in a chamber that is separated from another chamber by a suitable membrane, then detecting the amount of the compound reached the other chamber via passive diffusion across the membrane.…”

Section: Resultsmentioning

confidence: 99%

Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds

Farag

Hassan

Ahn

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC50 value of 1.97 µM against M-NFS-60 cells and good GIT absorption with Pe value of 19.0 ± 1.1 × 10−6 cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.

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“…The role of ROS was highlighted by demonstrating rescue of A␤-induced loss of axonal mitochondrial movement upon administration of Probucol, an antioxidant agent [466]. As a result of these observations, various studies embarked on targeting CypD/mPTP inhibition as potential treatment for neurodegenerative diseases [467,468].…”

Section: By Potentiating Mitochondrial Permeability Transition Pore Fmentioning

confidence: 99%

Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

Cioffi

Adam

Broersen

2019

JAD

146

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Alzheimer's disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-␤ deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer's disease and identifies genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer's disease-related oxidative stress.

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Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction

Cited by 29 publications

References 46 publications

Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress

Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress

Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds

Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

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