Abstract
•Synthesis of five hydrazinylidene-benzothiazinedione derivatives.•Diverse supramolecular networks of noncovalent interactions.•Assessment of energetic properties of the supramolecular dimers using QTAIM/NCI plot methods.•Compound 9b emerged as the lead inhibitor with strong efficacy.•Molecular docking analysis revealed several key interactions within the active site of urease.
The intricate role of noncovalent interactions in numerous fields including chemistry, biology, catalysis, material science, and medicinal chemistry provides a continuous impetus towards the discovery of new synthons that stabilize the supramolecular architectures. In this regard, the current work presents a series of five hydrazinylidene-benzothiazinedione derivatives encompassing a wide plethora of noncovalent interactions. Despite the configurational similarity of their hydrazinylidene-benzothiazinedione component, the five crystallographic packing arrangements of 7a–c and 9a,b are unique. The principal intermolecular interactions are CH⋯O hydrogen bonds and weak CH···π interactions (Malone Type III). Inversion dimers based on CH⋯Cl interactions form for 7b while CH⋯N and CH⋯S interactions in 9a were also observed. Furthermore, the energetic properties of the supramolecular dimers, centrosymmetric (antiparallel oriented) arrangements in 7a and 7b while parallel oriented arrangements in 9a and 9b have been examined using a combined QTAIM/NCI plot methods. The medicinal chemistry potential against urease enzyme revealed compound 9b as the lead inhibitor with strong efficacy (IC50 = 0.92 ± 0.03 µM). In vitro results were complemented with molecular docking revelations where several key interactions were observed between the potent ligand and active site amino acids. ADMET profile also described compounds 7b and 9b as the best molecules with promising druglike profile.
This manuscript presents the synthesis and analysis of noncovalent interactions in hydrazinylidene-benzothiazinediones supported by QTAIM/NCIplot method followed by biochemical and in silico assessment against urease enzyme. [Display omitted]