In silico safety profiling of triazolo/tetrazoloquinazolinederivatives : computational toxicity assessment for novel anti-inflammatory, venotonic drug development

Abstract

Previous molecular docking studies demonstrated that hetaryl/cycloalkyl/spiro [1, 2, 4] triazolo [1,5-c] quinazoline carboxylic acids' salts exhibit superior cyclooxygenase-2 (COX-2) binding affinities, with compounds KB-282 and 488 achieving exceptional performance (-11.9 and -10.4 kcal/mol, respectively). However, clinical development of COX-2-targeting compounds requires comprehensive safety evaluation given documented cardiovascular and hepatotoxicity concerns. This study employed computational toxicity assessment using admetSAR 3.0 to evaluate safety profiles of ten triazolo/tetrazoloquinazoline derivatives alongside three reference compounds across six critical endpoints: cardiotoxicity, hepatotoxicity, neurotoxicity, mutagenicity, respiratory toxicity, and nephrotoxicity. Structure-activity relationships revealed, that spiroindoline-tetrazoloquinazoline scaffolds represent promising platforms for optimization. The integration of molecular docking predictions with toxicity assessment enables rational identification of compounds with balanced efficacy-safety profiles, critical for advancing novel anti-inflammatory and venotonic therapeutics. Further investigation is warranted to validate computational predictions and optimize lead compounds toward preclinical development. Keywords. Spiro[1, 2, 4] triazolo [1,5-c] quinazolines, toxicity prediction, ADMETlab 3.0.