Initial Discovery and Characterization of Novel Spirotriazoloquinazolines as Potential Neuroprotectors: Synthesis, Computational Screening, and Preliminary In Vivo Evaluation

<jats:p>Ketamine anesthesia frequently causes postoperative cognitive dysfunction as the primary clinical concern, with potential broader applications to trauma-related cognitive disorders. This study explores novel neuroprotectives, targeting multiple pathways through design, synthesis, and evaluation of forty 2'-R-6'H-spiro(cycloalkyl/heterocyclyl)[1,2,4]triazolo[1,5-c]quinazolines. Molecular docking showed superior binding affinities to GluA3 compared to references, additionally to favorable drug-likeness ADMET. Selected compounds were tested in ketamine-induced cognitive impairment rat models with assessment in vivo. Compounds 25, 26, and 32 effectively normalized ketamine-disrupted behavioral parameters, reducing anxiety and improving cognitive function more effectively than piracetam and fabomotizole. 31 showed potent anti-inflammatory effects (72% reduction in IL-1β, 80% - in caspase-1), while 26 enhanced cell survival pathways (96% increase in Bcl-2) and hypoxic adaptation (3.5-fold increase in HIF-1 mRNA). These novel spirotriazoloquinazolines function as positive modulators of cognitive-enhancing receptors (GABA(A), GluA3), rather than direct antagonists, demonstrating neuroprotective properties through anti-inflammatory, anti-apoptotic, and adaptive pathway modulation, while definitive classification requires functional validation.</jats:p>