Pyridazin-3(2H)-one Derivatives: Computational ADME-Tox, Molecular Docking, Drug-Likeness Analysis, Molecular Dynamics Simulations, and Assessment of Their Antitubercular Potential

Pyridazinones are a versatile class of heterocycles that have been gaining interest in the field of antimicrobial compound development. In the present study, a holistic in silico strategy has been developed for the assessment and prioritization of a small dataset of novel pyridazinones as promising antitubercular compounds against Mycobacterium tuberculosis, which have been developed in the year 2025. Each of the selected compounds has the potential for showing a therapeutic effect. Initially, the compounds have been analyzed using molecular docking studies in order to understand the binding orientations and the major ligand-protein interaction. The compounds have been filtered using the principle outlined in the "rule of five". At the same time, ADMET predictions were carried out to estimate the oral bioavailability, safety risks, and metabolite stability, allowing the early removal of candidates with undesirable absorption and safety properties. The docking score for the original ligand and its co-crystallized form in the protein was -9.6 kcal/mol, whereas a number of designed ligands with a pyridazinone backbone showed higher predictions for the binding energy, ranging from better than -9.6 kcal/mol to a value of -11.4 kcal/mol. Thus, the current candidates showed promising binding properties and an acceptable pharmacokinetic profile and lack of toxicity.