N'-Isonicotinoylpicolinohydrazonamide: Synthesis, Crystal Structure, Dft and Admet Studies, And in Silico Inhibition Properties Toward a Series of COVID-19 Proteins

Abstract

In this work, synthesis as well as detailed structural and computational analyses of the novel isoniazid derivative, namely N'-isonicotinoylpicolinohydrazonamide (1), are reported. The obtained compound was examined by microanalysis, IR, 1H NMR spectroscopy and single crystal X-ray diffraction. The crystal packing was studied by the Hirshfeld surface analysis. Molecules in the crystal structure of 1 are linked through N–H∙∙∙O and N–H∙∙∙N hydrogen bonds, and π∙∙∙π interactions, yielding a 1D supramolecular chain. According to the Hirshfeld surface analysis, crystal packing of 1 is primarily dictated by H∙∙∙H, H∙∙∙C, H∙∙∙N and H∙∙∙O contacts, of which the latter three contacts are highly favoured. The crystal packing is further characterized by highly favoured C∙∙∙C contacts. Compound 1 was also studied using DFT in gas phase, which revealed its pronounced electrophilic features. The most electron-rich (nucleophilic) sites were revealed for the carbonyl oxygen atom, and 4-pyridyl and imine nitrogen atoms, while the most electron-deficient (electrophilic) sites were found for the NH and NH2 hydrogen atoms. Compound 1 was predicted to belong to a fourth class of toxicity and exhibits negative blood-brain barrier penetration and positive gastrointestinal absorption property. In silico molecular docking was applied to probe 1 as a potential inhibotor of a series of the SARS-CoV-2 proteins and it was found that 1 is potentially active against all the applied proteins with the best activity against Nonstructural protein 3 (Nsp3_range 207–379-MES). It was also established that the best docking scores for 1 were found for the cavities, where initial ligands were located, except for the Papain-like protease (PLpro). The best binding affinity of the latter protein with 1 was revealed for the other cavity with about 0.8 kcal/mol being more efficient. Molecular dynamics simulations were also applied to evaluate the stability of complexes PLproI–1, PLproII–1 and Nsp_range 207–379-MES–1. Complex PLproI–1 was found to be highly unstable, while complexes PLproII–1 and Nsp_range 207–379-MES–1 are stable.

Keywords: isoniazid, crystal stryctyre, Hirshfeld surface analysis, DFT, COVID-19