Indanone Compounds Show Promise Against Parkinson’s and Alzheimer’s in Animal Studies

A team of medicinal chemists at Panjab University in Chandigarh, India, has reported that a family of synthetic molecules built around the indanone scaffold can protect the brain in animal models of both Parkinson’s disease and Alzheimer’s disease. The study, published in the journal Discover Chemistry, combined careful organic synthesis with behavioural testing, biochemical assays, histopathology and computational modelling to build a multi-layered case for the compounds’ neuroprotective potential. The work, led by Shalinee Chandra, Ranjit Singh and Ranju Bansal of the University Institute of Pharmaceutical Sciences, was supported by the Department of Health Research and the University Grants Commission of India.

The design of the molecules was deliberately inspired by existing drugs. Donepezil, a mainstay Alzheimer’s therapy, owes much of its acetylcholinesterase-inhibiting power to its dimethoxy groups, while the anti-Parkinsonian drugs selegiline and rasagiline depend on a propargyl group to selectively and irreversibly inhibit monoamine oxidase B, thereby raising dopamine levels in the brain. A hybrid drug called TV-3326, which fuses features of rivastigmine and rasagiline, is undergoing clinical trials for its anti-apoptotic, neuroprotective effects in Alzheimer’s disease. Taking these structural lessons together, the Chandigarh group set out to create indanone derivatives bearing arylidene groups and, in several cases, a propargyloxy substituent, hoping to obtain multitarget-directed agents capable of attacking several pathological processes at once.

Synthesis of the compounds was accomplished through well-established base-catalysed aldol condensations. Mixing indanone or 5-methoxyindanone with the appropriate aldehyde and sodium hydroxide in methanol yielded the 2-arylidene indanones 1a through 1d. An interesting quirk emerged with the pyridyl aldehydes: rather than stopping at the simple aldol product, the reaction mixture underwent a further base-catalysed nucleophilic addition to form dimeric spiro compounds as the major products, whose structures were confirmed by nuclear magnetic resonance spectroscopy. For the propargyloxy series 3a through 3c, the researchers first prepared hydroxybenzylidene intermediates and then alkylated the phenolic oxygen with propargyl bromide in refluxing ethyl methyl ketone using potassium carbonate. Spectroscopic fingerprints, including the alkyne carbon-hydrogen stretch near 2112 wavenumbers in the infrared spectra and characteristic alkyne proton signals near 2.57 parts per million in the proton NMR, confirmed the successful installation of the propargyl ether moiety in each final compound.

To test anti-Parkinsonian activity, the team used mice treated with MPTP, a neurotoxin that damages dopaminergic neurons in the substantia nigra and produces the locomotor deficits characteristic of Parkinson’s disease. Mice received daily intraperitoneal injections of the test compounds at 20 milligrams per kilogram for seven days alongside the toxin, and their movement was assessed with an actophotometer and a rotarod apparatus. MPTP alone drastically reduced ambulation, rearing and rotarod performance, but co-treatment with the indanones significantly restored all three measures. The standout was compound 3b, the para-propargyloxybenzylidene indanone, which achieved an ambulation score of 229.66, rearing of 50.73 and a rotarod response of 249.33, actually exceeding the reference drug selegiline in rearing and rotarod performance. The remaining analogues also improved locomotion, though generally falling short of the standard drug.

For Alzheimer’s-like pathology, the researchers turned to rats injected with amyloid-beta peptide 1-42 directly into the hippocampus, a procedure that triggers glial activation, oxidative stress, chronic neuroinflammation and the loss of spatial learning and memory. Cognitive function was evaluated with the novel object recognition test and the elevated plus maze. Amyloid-treated rats showed a collapsed discrimination index and increased percentage of initial transfer latency, but seven days of treatment with the indanones significantly improved both measures. Here the most active compounds were the 5-methoxyindanones: compound 1d, bearing a para-methoxybenzylidene group, and compound 3c, carrying a meta-propargyloxy substituent, restored discrimination indices of 0.23 and 0.28 respectively, approaching but not surpassing the reference drug rivastigmine, which scored 0.38.

Biochemical analysis of brain homogenates revealed how the compounds were working at the cellular level. Neurotoxins such as MPTP and amyloid-beta disrupt the normal balance of oxidative markers, antioxidant enzymes and cholinergic signalling. Treatment with the indanones upregulated the antioxidant enzymes superoxide dismutase and glutathione peroxidase, downregulated lipid peroxidation as measured by malondialdehyde, scavenged excess reactive oxygen species, reduced nitric oxide levels and countered the overactivity of acetylcholinesterase. According to the authors, these biochemical shifts prevent calcium influx and mitochondrial depolarization, halting cell lysis and preserving neuronal membrane integrity, which ultimately translates into improved motor and cognitive function. Compound 3b again produced the greatest restoration of biochemical parameters in the MPTP mice, while 1d and 3c performed best in the amyloid-treated rats, mirroring the behavioural results.

Histopathological examination of brain sections under light microscopy provided visual confirmation of the protection. Brains from MPTP-treated mice showed degenerative changes in neurons due to oedema fluid, overactivation of astrocytes and microglia, and depletion of neuronal cells. In contrast, mice co-treated with compound 3b displayed far fewer neurodegenerative changes. Similarly, the hippocampi of amyloid-injected rats exhibited glial activation, chronic inflammation and apoptosis, while rats receiving compounds 1d or 3c showed much less neuroinflammation and no severe neuronal degeneration. These tissue-level observations aligned neatly with the behavioural and biochemical data, strengthening the overall evidence that the compounds genuinely shield neurons rather than merely masking symptoms.

Computational studies added a mechanistic dimension. An ADME analysis using the QikProp module of Schrödinger’s Maestro software showed that all the compounds obey Lipinski’s rules and possess predicted brain-to-blood partition coefficients above 0.3, indicating good penetration of the blood-brain barrier, an essential property for any central nervous system drug candidate. Molecular docking against the crystal structures of monoamine oxidase B, human acetylcholinesterase and beta-secretase revealed strong binding interactions. Compound 3b engaged MAO-B through pi-pi stacking with Trp-388 and polar contacts with Lys-296 and Val-294, closely mimicking the binding mode of the co-crystallized ligand safinamide. In acetylcholinesterase, compounds 1d and 3c formed pi-pi stacking interactions with Trp-286 and Tyr-337 within the enzyme’s 20-angstrom-deep gorge, while in beta-secretase they contacted Tyr-71, Tyr-198 and Phe-108 through a combination of stacking, hydrogen bonding and polar interactions.

Molecular dynamics simulations of 100 nanoseconds confirmed that these binding poses were stable over time. Root mean square deviation values stayed within the optimal range, and root mean square fluctuation values for individual amino acid side chains remained below 5 angstroms, indicating minimal conformational drift. Key interactions were retained throughout the simulations: compound 3b held its pi-pi stacking with Trp-388 of MAO-B for 41 percent of the simulation and its electrostatic contact with Lys-296 for 43 percent, while compound 1d maintained pi-pi stacking with Tyr-337 of acetylcholinesterase for 78 percent of the run and hydrogen bonding with Phe-295 for 75 percent. The consistency between docking and simulation lent computational credibility to the proposed mechanism of action.

The study’s structure-activity conclusions are clear: placing a propargyloxy group on the arylidene ring and adding a 5-methoxy substituent on the indanone nucleus both shape the pharmacological response, with the para-propargyloxy arrangement favouring anti-Parkinsonian activity and the 5-methoxy scaffold favouring cognitive protection. The authors caution that in vitro enzyme assays against MAO-B, acetylcholinesterase and beta-secretase will be needed to confirm the mechanism directly, and the path from rodent models to human therapy remains long. Nevertheless, the convergence of behavioural rescue, biochemical normalization, preserved brain histology and stable computational binding makes these indanone derivatives a compelling new platform for designing the next generation of multitarget neuroprotective drugs, offering a rare single-scaffold approach to two of the most devastating neurodegenerative diseases of our time.

Subject of Research: Neuroprotective evaluation of arylidene indanone derivatives in animal models of Parkinson's and Alzheimer's disease

Article Title: Experimental and computational insights into neuroprotective properties of arylidene indanone derivatives

Article References: Chandra, S., Singh, R., & Bansal, R. (2026). Experimental and computational insights into neuroprotective properties of arylidene indanone derivatives. Discover Chemistry, 3(1), Article 439. https://doi.org/10.1007/s44371-026-00885-1

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00885-1

Keywords: indanone derivatives, neuroprotection, Parkinson's disease, Alzheimer's disease, MPTP mouse model, amyloid-beta, acetylcholinesterase, MAO-B, beta-secretase, molecular docking, oxidative stress, drug design