Unexpected products using Biginelli reaction: Synthesis, antimicrobial potency, docking simulation, and DFT investigations of some new amidopyridines

Abstract

The Biginelli reaction of 3-oxo-N-(2-pyridyl)butanamide with thiourea (or urea) and some aromatic aldehydes afforded new chemical skeletons containing tetrahydropyrimidine, pyridine, and carboxamide pharmacophoric moieties. The expected products of this reaction were not isolated in the case of 4-nitrobenzaldehyde, pyridine-2-carbaldehyde, and thiophene-2-carbaldehyde; rather the corresponding acrylamide derivatives were obtained. Chemical structures of the newly synthesized hybrids were elucidated by FT-IR, NMR spectroscopy in addition to mass spectrometry and elemental analyses. The in-vitro antimicrobial activity showed that the products were highly active against the tested pathogens that were confirmed through molecular docking simulation with different proteins such as PDBID:3t88, 2wje, 1tgh, and 4ynt which showed a different binding affinity with attraction of amino acids of proteins. Furthermore, the optimization of different pyridine carboxamides utilized a DFT/B3LYP-6311(G) basis set to know the cyclization of butanamide 1 with thiourea and different aldehydes in the presence of electron-donating/withdrawing groups which affected of the expected products with different transition states. Moreover, the determination of the energy gap and physical descriptors of these pyridine carboxamide derivatives showed the stability of tetrahydropyrimidines 2a,b due to the presence of donating groups which enhanced the activity and stability. Determination of the ESP and MEP of compounds 2a,b confirmed a correlation with biological evaluations.