<i>N'</i> ‐Isonicotinoylnicotinohydrazonamide: Synthesis, Crystal Structure and Computational Studies

ABSTRACT An Isoniazid derivative, N' ‐isonicotinoylnicotinohydrazonamide ( 1 ), was synthesized via a reaction between Isoniazid and 3‐cyanopyridine. It was established that 1 adopts a keto conformation in the solid state, forming a 2D supramolecular network stabilized by N─H⋯O and N─H⋯N hydrogen bonds. The NMR studies indicated the presence of two conformational isomers, a behavior attributed to the greater flexibility imparted by the meta ‐positioned nitrogen in the nicotinoyl moiety, in contrast to its rigid picolinoyl‐containing isomer 2 , which was reported by us previously. Hirshfeld surface analysis quantified the intermolecular interactions of 1 , identifying H⋯H, H⋯C, H⋯N, and H⋯O contacts as the most significant contributors to the crystal packing. DFT calculations provided insights into the electronic structure, molecular electrostatic potential, and global reactivity descriptors, which characterized 1 as a strong electrophile. A combined QTAIM/NCI analysis confirmed the presence of prominent intramolecular interactions. In silico ADMET profiling of 1 predicted a favorable pharmacokinetic profile with high gastrointestinal absorption but potential hepatotoxicity and neurotoxicity. Molecular docking studies against key Mycobacterium tuberculosis proteins, viz. Proteasomal ATPase Mpa, Serine/threonine‐protein kinase, and Arabinosyltransferase, demonstrated that 1 exhibits superior binding affinity and ligand efficiency compared to the parent Isoniazid, suggesting its potential as a promising lead compound for anti‐tuberculosis drug development.