Quantum Chemistry-Guided Design of Nitrogen-Containing Heterocycles as Anticancer Agents: From Reactivity Descriptors to Biological Validation

Nitrogen-containing heterocycles, including pyrazoles, pyrimidines, isoxazoles, thiazoles, and naphthyridines, constitute the dominant structural class among approved anticancer agents, owing to their versatile pharmacophoric geometry, capacity to engage validated oncological targets such as cyclin-dependent kinases, histone deacetylases, topoisomerases, and receptor tyrosine kinases, and amenability to systematic substitution. Traditional lead discovery in this chemical space has depended largely on empirical high-throughput screening, which is both resource-intensive and provides limited a priori insight into the electronic and reactivity determinants of biological activity. Quantum chemical methods, particularly density functional theory (DFT), now offer direct access to frontier molecular orbital parameters, chemical hardness and softness, electrophilicity indices, Fukui functions, and molecular electrostatic potential maps. These reactivity descriptors encode the electronic properties most relevant to target recognition and binding, enabling rational prioritization of candidate structures before synthesis or biological testing is undertaken.Despite growing application of DFT and molecular docking in anticancer drug discovery, the field lacks a consolidated framework that systematically links quantum chemical characterization to ADMET prediction, targeted synthesis, and rigorous pharmacological validation. Computational results frequently remain disconnected from experimental follow-through, particularly from mechanistic studies addressing mode of action, target engagement, and selectivity, limiting their translational relevance.This Research Topic aims to bring together original research and critical reviews that exemplify the full discovery pipeline for heterocyclic anticancer candidates: from DFT-derived reactivity descriptor analysis and structure-based virtual screening, through pharmacokinetic profiling and synthesis, to in vitro cytotoxicity, mechanistic target engagement, and where available, in vivo validation. The collection will map current best practices, identify methodological gaps, and promote quantum chemistry-guided rational design as a reproducible framework for advancing nitrogen-containing heterocycles toward pharmacologically validated anticancer candidates.Themes of interest include:• DFT-derived reactivity descriptor profiling (HOMO-LUMO energies, chemical hardness, electrophilicity, Fukui functions, molecular electrostatic potential) of novel heterocyclic scaffolds• Structure-based and multi-target molecular docking against validated targets such as CDKs, HDACs, topoisomerases, and receptor tyrosine kinases• In silico ADMET and drug-likeness assessment• Synthesis of computationally prioritized hits• In vitro cytotoxicity evaluation demonstrating selectivity across multiple cancer cell lines• Mechanistic studies addressing mode of action and target engagement.In vivo pharmacological data are particularly encouraged where available. Original Research, Review, and Methods articles are welcome. In accordance with the section’s requirements, all submissions must include experimental anticancer biological data; manuscripts reporting computational results alone will not be considered. Studies targeting multi-drug-resistant cancer models or underexplored oncological targets are also of strong interest. Topic editors: Sumaiya Tabassum, Dr. Bonny Patel, Ewa Dresler Source: https://www.frontiersin.org/research-topics/83437/quantum-chemistry-guided-design-of-nitrogen-containing-heterocycles-as-anticancer-agents-from-reactivity-descriptors-to-biological-validation