Fabomotizole

This study describes the rational design, synthesis, and evaluation of forty 2′‐R‐6′ H ‐spiro(cycloalkyl/heterocyclyl)[1,2,4]triazolo[1,5‐ c ]quinazolines as potential neuroprotective agents targeting multiple receptor systems implicated in cognitive dysfunction. The molecular design integrated structural features from established nootropic and anxiolytic pharmacophores to create compounds with putative multi‐target activity. In silico ADMET analyses assessed drug‐likeness parameters, while molecular docking studies evaluated binding interactions with nine neuroreceptor targets: glutamate GluA3, GABA(A)R, dopamine D2, serotonin 5‐HT1A and 5‐HT7, cannabinoid CB2, muscarinic M2 acetylcholine, corticotropin‐releasing factor receptor 1 (CRF1R), and metabotropic glutamate receptor 5 (mGluR5). Based on computational predictions, selected compounds underwent preliminary in vivo screening using a ketamine‐induced cognitive impairment model in rats. Behavioral assessments examined anxiety‐related responses and cognitive performance relative to piracetam and fabomotizole controls. Biochemical analyses measured inflammatory markers (IL‐1β, caspase‐1), cell survival indicators (Bcl‐2), and hypoxic adaptation responses (HIF‐1 mRNA). Docking studies indicated favorable binding profiles across tested receptor targets compared to reference ligands, with calculated affinities suggesting potential modulatory interactions. The experiments showed that compounds 25 , 26 , and 32 attenuated ketamine‐induced behavioral alterations, demonstrating effects in anxiety reduction and cognitive performance that appeared numerically greater than piracetam and fabomotizole, though the magnitude and statistical robustness of these differences require further characterization. Compound 31 reduced IL‐1β expression by 72% and caspase‐1 by 80% relative to ketamine‐treated controls. Compound 26 increased Bcl‐2 expression by 96% and HIF‐1 mRNA levels by 3.5‐fold compared to control conditions. These findings suggest that spirotriazoloquinazolines may function as positive modulators at cognitive‐enhancing receptors, potentially exerting neuroprotective effects through anti‐inflammatory and anti‐apoptotic mechanisms. Further investigation is necessary to validate the observed effects, establish dose–response relationships, and elucidate the molecular mechanisms underlying the apparent neuroprotective properties of these compounds. image

Although the contribution of sigma1 receptor (Sig-1R) to afobazole's cardioprotection has been meticulously investigated, Sig-1R-mediated cardioprotective effect of afobazole against sunitinib cardiotoxicity has not been studied yet. Hence, we aimed at studying the potential modulatory impact of afobazole on Sig-1R to combat sunitinib-induced endoplasmic reticulum (ER) stress, maladaptive autophagy, and hyperactivation of neutrophils that ends up with neutrophil extracellular traps (NETs) formation. Pre-treatment with afobazole attenuated sunitinib-induced cardiotoxicity and enhanced cardiac function via significant reduction of TNNT2 and CK-MB, and restoration of nearly normal hemodynamic measurements. Afobazole-mediated Sig-1R activation mitigated the ER stress sensor, IRE1α activation and its downstream (ASK/JNK/AP-1) pathways along with caspase-3 and FK18. Subsequently, afobazole hindered NETs formation by prohibiting ER stress-induced activation of caspase-2 and pro-inflammatory cytokines; IL-1β and TNFα, as indicated by the significant reduction of NETs' specific components, namely, PAD4, NE, and MPO, along with the NETs' specific marker Cit H3. Afobazole also downregulated sunitinib-induced maladaptive autophagy, as reflected by reducing the expressions of autophagy-regulating proteins (ATG5 and ATG7) and microtubule-associated protein light chain 3 (LC3-II/I) ratio as well p62 upregulation. Furthermore, afobazole exhibited a cardioprotective effect by restoring nearly normal CCN2 level that was degraded by Tollip and HMGB1. The above-mentioned outcomes triggered by afobazole were clearly negated upon administration of the Sig-1R antagonist (BD1047), confirming that Sig-1R activation predominantly mediates the observed cardioprotective effects. Afobazole demonstrated efficacy in mitigating sunitinib-induced cardiotoxicity, as evidenced through the enhancements in hemodynamic stability, reduction of ER stress, amelioration of maladaptive autophagy, and inhibition of NETs formation.