Cooperative assemblies featuring hydrogen bonding and C[sbnd]H…π interactions in 2-(methanesulfonamido)benzohydrazide derivatives: Experimental, computational and biochemical assessment

Munir R., Zaib S., Khan I., Yousaf A., McAdam C. J., Yeow C. H. S., ...More

Journal of Molecular Structure, vol.1295, 2024 (SCI-Expanded) identifier

  • Publication Type: Article / Article
  • Volume: 1295
  • Publication Date: 2024
  • Doi Number: 10.1016/j.molstruc.2023.136752
  • Journal Name: Journal of Molecular Structure
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, INSPEC
  • Keywords: Benzohydrazide, Computational analysis, Crystal packing, C–H…π interactions, H-bonding contacts, Noncovalent interactions, Urease inhibition
  • Hacettepe University Affiliated: Yes


The significant involvement of noncovalent interactions in catalyst design and synthesis of materials provides a fundamental impetus to explore various synthons that produce complex frameworks. Therefore, in the present work, cooperative assemblies of two methanesulfonamide containing benzohydrazide derivatives (6 and 7) were designed and analyzed. These compounds were synthesized through a straightforward approach using hydrazide 3 and 4-methyl-2-acetylthiophene (4) and 4-methoxyacetophenone (5) in refluxing ethanol. Both compounds were characterized by FTIR, NMR, LCMS and X-ray crystallography. Noncovalent interactions such as C[sbnd]H…π interactions and hydrogen bonding played a crucial and dominant role in the structural design of complex molecular architectures. X-ray crystal analysis reveals the presence of an intramolecular classical N[sbnd]H…O strong hydrogen bond and a weaker C[sbnd]H…O interaction in compounds 6 and 7. The N[sbnd]H…O arrangement of hydrazone-hydrazone cores also facilitates a C[sbnd]H…π close contact between the sulfonamide methyl group and the proximal benzoyl aromatic ring. Moreover, the methoxy group in 7 is also involved in C[sbnd]H…O/S and C[sbnd]H…π interactions. Hirshfeld surface analysis further revealed the involvement of these noncovalent contacts in the stabilization of molecular topology of both compounds. The energetic features of noncovalent interactions were characterized by DFT calculations while molecular electrostatic potential (MEP), QTAIM and NCIPlot computational tools rationalized the structural assemblies found in the crystal packing of both compounds. Furthermore, the biological assessment against urease enzyme revealed 13-fold superior inhibition with an IC50 value of 1.67 ± 0.19 µM for compound 6. In vitro inhibitory data was complemented with an in silico modeling where the observed interactions between the active site amino acids and compound 6 underscored the importance of heteroaryl (thienyl) component for strong inhibitory effects. Finally, the assessment of pharmacokinetic parameters proposed compound 6 as a suitable druggable inhibitor for further evaluation.