P3‐357: Design, synthesis, and biological evaluation of novel fused‐ring systems to treat Alzheimer's disease
Bibliographic record
Abstract
Evidence suggests that in order to prevent Alzheimer's disease (AD) progression one has to develop novel agents to target multiple AD pathways as disease-modifying agents. We are developing fused heterocyclic ring systems to target the cholinergic, metal and oxidative stress mediated neurotoxicity. Structure activity data for a library of novel heterocyclic molecules and their potential as disease-modifying agents will be presented. Computational/molecular modeling studies: The structure-based design (SBD) module is used to design novel fused ring systems and the ligand-enzyme binding interactions with monomeric human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes are investigated. Synthetic Organic Chemistry: Currently, a synthetic protocol has been developed to prepare acridine derivatives. The synthesis involved reduction of nitro-substituted-benzoic acid derivatives to aminobenzoic acid derivatives which was reacted with cyclohexanone in presence of phosphorous oxychloride to obtain 9-chloro-substituted tetrahydroacridine intermediate which was further reacted with various peripheral anionic site and antioxidant pharmacophores to afford target molecules possessing varying steric and electronic properties Cholinesterase inhibition assay: Compounds are screened for inhibition of mammalian AChE and BuChE. The concentrations of the test compounds causing 50% inhibition (IC50, μM) are calculated.Metal chelation and antioxidant property evaluation: Metal-chelation ability is evaluated using UV spectroscopy whereas antioxidant properties are evaluated using oxygen radical absorbance capacity assay (ORAC-FL). We have synthesized compounds that were characterized via analytical techniques including nuclear magnetic spectroscopy and mass spectrometry. Purity of the compounds is assessed by HPLC analysis. Anticipated results will include a library of acridine derivatives varying in chemical and physical properties. Molecular modeling studies have indicated the central fused acridine ring undergoes favourable interactions within the catalytic site of AChE enzyme. Preliminary data on their ability to inhibit both AChE and BuChEs, their ability to chelate metals and antioxidant properties along with detailed enzyme-ligand binding investigations will be discussed.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".