Rational Design of Safer Bioactive Scaffolds: Integrating Synthesis, Pharmacology, and Computational Toxicity Prediction

Balancing therapeutic potency with organ safety remains a central challenge in medicinal chemistry, particularly for drugs targeting inflammation, cancer, and cardiovascular disease, where off-target liabilities are common. Traditionally, toxicity was assessed only after a lead compound was synthesized, often causing late-stage attrition. Increasingly, chemists address this earlier by pairing multistep organic synthesis of heterocyclic and urea/thiourea-based scaffolds with computational safety assessment, including molecular docking, molecular dynamics, and quantum chemical (DFT) calculations. This integrated approach allows toxicophores, reactive metabolites, and off-target interactions, such as gastrointestinal or hepatic liabilities, to be identified early, embedding safety directly into scaffold design. This Research Topic aims to gather research linking the synthesis of novel bioactive molecules to their predicted and validated safety profile. Scaffolds of interest include dihydropyridine, benzothiadiazine, benzofuran, and quinoline hydrazone derivatives, as well as related heterocyclic systems. We encourage structural modifications designed to reduce organ toxicity while preserving or enhancing biological efficacy against targets in inflammation, cancer, infection, or cardiovascular physiology. We welcome Original Research, Review, Mini Review, Methods, and Perspective articles. Contributions should combine wet-lab synthetic chemistry and pharmacological testing with computational modeling (docking, ADMET/QSAR, DFT) to rationalize biological outcomes. Specific areas of interest include, but are not limited to:• Design and Synthesis: Novel bioactive scaffolds (e.g., ureas, thioureas, sulfonylureas, dihydropyridines, benzothiadiazines, benzofurans, quinoline hydrazones) evaluated for anti-inflammatory, anticancer, antibacterial, hepatoprotective, or vasorelaxant activities with improved safety margins. • Target & Off-Target Engagement: Molecular docking and molecular dynamics (MD) simulations rationalizing therapeutic engagement (e.g., COX-2, ERK2, carbonic anhydrase, KATP channels, voltage-gated calcium channel) and off-target risk profiles. • In Silico Safety Profiling: Predictive ADMET, QSAR, and machine learning models guiding lead optimization toward organ-specific safety (e.g., hepatic or gastrointestinal tolerance). • Quantum Chemical Calculations: DFT and reactivity descriptors characterizing molecular stability, electronic mechanisms, and reactive metabolite toxicity. • Multi-Target Strategies: Dual- or multi-target agents designed to achieve a widened therapeutic window and reduced liability profiles. To maintain high biological and chemical rigor, purely computational manuscripts lacking experimental validation (or concrete experimental rationale), meta-analyses, clinical cohort studies, and manuscripts lacking a clear chemical design component fall outside the scope of this collection. Topic editors: Adnan Cetin, Widad Sobhi, Smail Khelili, Stiti Mohamed Zakaria Source: https://www.frontiersin.org/research-topics/84530/rational-design-of-safer-bioactive-scaffolds-integrating-synthesis-pharmacology-and-computational-toxicity-prediction