In Silico Evaluation of Benzamide Derivatives as Potential Analgesic and Antipyretic Alternatives to Paracetamol with Reduced Toxicity Risk
Zobayed Islam, Sajeda Sathi, Supriya Sharmin Tushi, S. M. Naim Uddin · ChemistrySelect · 2025
Abstract Paracetamol (acetaminophen) is widely used for analgesia and fever control but has well‐documented toxicity risks in some settings. We performed an in silico screen to identify benzamide‐scaffold compounds with potential paracetamol‐like analgesic/antipyretic activity and improved safety indicators.A library of 116 benzamide derivatives was compiled from public databases and the literature. Molecular docking was performed using human COX‐1 (used as a structural surrogate for COX‐3) to prioritize compounds by predicted binding. Top hits were further evaluated by ADME and toxicity prediction tools (pkCSM, ProTox‐3). All computational methods, selection criteria, and interpretive thresholds are documented in Methods and Supporting Information. Several benzamide derivatives showed favorable docking poses in the COX active site and a subset displayed predicted ADME/Tox profiles that compare favorably to paracetamol. Predictions are presented as quantitative probabilities (e.g., ProTox‐3 endpoint probabilities, pkCSM descriptors) rather than binary assertions.The computational results identify promising benzamide scaffolds for follow‐up experimental validation. We emphasize that the findings are hypothesis‐generating: wet‐lab enzymatic, cellular and in vivo assays will be required to confirm analgesic/antipyretic activity and safety.