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

Abstract

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.

Omarigliptin Mitigates 6-Hydroxydopamine- or Rotenone-Induced Oxidative Toxicity in PC12 Cells by Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Actions

“…To estimate whether OMG exerted any cytotoxicity, PC12 cells were treated with OMG at a series of concentrations in culture media containing low serum (1% FBS, 1% HS, 100 IU/mL penicillin, and 100 μg/mL streptomycin) for 24 h. Control cells were treated with the same media containing low serum and an equivalent volume of DMSO (0.5%). The protective effects of OMG against 6-OHDA- or rotenone-induced toxicity in PC12 cells were evaluated as reported previously [ 30 , 35 ]. Briefly, cells were pretreated with OMG at various concentrations for 4 h and subsequently exposed to 6-OHDA (50 μM) or rotenone (1 μM) for 24 h. The effect of ZnPP, an HO-1 inhibitor, on the protective effects of OMG against 6-OHDA- or rotenone-induced toxicity was evaluated as reported [ 30 ].…”

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

“…Alternatively, MAO-B inhibitors may be a better treatment choice for early PD, because of their favorable safety profile and potential neuroprotective properties. Many attempts are currently being undertaken to synthesize novel MAO-B inhibitors with neuroprotective properties, providing promising examples of multitarget-directed pharmacological interventions for PD treatment [ 10 , 11 ]. Low doses of glutamate antagonists have been shown to slow the progression of PD by reducing DA denervation in the striatum [ 12 ].…”

Diclofenac derivatives as concomitant inhibitors of cholinesterase, monoamine oxidase, cyclooxygenase-2 and 5-lipoxygenase for the treatment of Alzheimer's disease: synthesis, pharmacology, toxicity and docking studies

“…Compound 12 was treated with 1,4-dibromo butane in the presence of TEA in dichloromethane (DCM) as solvent. The synthesized intermediate was further reacted with dihydropyrimidine-2-thiones (18)(19)(20)(21)(22), succinimide derivatives 23, 24 and tricyclic phenothiazine 25 to obtain the target compounds 26-33 (Scheme 3).…”

“…MAO-B expression is shown to be much higher in the hippocampus and cerebral cortex of Alzheimer's patients, accompanied with an excess of reactive oxygen species and hydrogen peroxide. [17][18][19] AD is currently untreatable and presently available anticholinesterase FDA approved drugs like donepezil, rivastigmine, galantamine and memantine, are single-target drugs that improve memory loss and cognitive functions whereas these are unable to completely cure dementia. In AD several relevant targets in various cell signaling pathways interact to form a network, thus making it difficult for single target drugs to cure the disease effectively.…”