Search for Potential Neuroprotectors for Correction of Cognitive and Behavioral Disorders After Ketamine Anesthesia Among 2′-R-6’H-Spiro(cycloalkyl-, heterocyclyl)[1,2,4]triazolo[1,5-<em>c</em>]Quinazolines: Fragment-Oriented Design, Molecular Docking, ADMET, Synthesis and <em>In Vivo</em> Study

Background: Ketamine anesthesia frequently causes postoperative cognitive dysfunction and behavioral disorders, with limited effective therapeutic options. This study explores novel neuroprotective compounds targeting multiple pathways in neurological disorders following ketamine anesthesia through the design, synthesis, and evaluation of 2'-R-6'H-spiro(cycloalkyl-, heterocyclyl)[1,2,4]triazolo[1,5-c]quinazolines. Methods: Using fragment-oriented design, we synthesized 40 spiro-triazoloquinazolines via [5+1]-cyclocondensation. Molecular docking assessed binding affinities to glutamate receptor GluA3, while ADMET analyses evaluated pharmacokinetic properties. Selected compounds were tested in a ketamine-induced cognitive impairment rat model with behavioral assessment via open field test. Neurobiochemical analyses measured inflammatory markers, apoptotic regulators, and gene expression in hippocampal tissue. Results: Molecular docking showed superior binding affinities to GluA3 compared to reference nootropics, while ADMET analyses confirmed favorable drug-likeness profiles. In vivo evaluation demonstrated compounds 25, 26, and 32 effectively normalized ketamine-disrupted behavioral parameters, reducing anxiety and improving cognitive function more effectively than piracetam and fabomotizole. Neurobiochemical analyses revealed compound-specific mechanisms: compound 31 showed potent anti-inflammatory effects (72% reduction in IL-1β, 80% reduction in caspase-1), while compound 26 enhanced cell survival pathways (96% increase in Bcl-2) and hypoxic adaptation (3.5-fold increase in HIF-1 mRNA). Structure-activity relationship analyses established that spiro-junction type and 2'-position substituent critically determine pharmacological profiles. Conclusions: These novel spiro-triazoloquinazolines demonstrate promising neuroprotective properties for treating cognitive and behavioral disorders associated with ketamine anesthesia through multiple mechanisms including anti-inflammatory, anti-apoptotic, and adaptive pathway modulation. Their superior efficacy compared to current treatments positions them as candidates for further development in post-anesthetic cognitive dysfunction and potentially in post-viral and trauma-related neurological conditions.