1-hydroxy-6,6-Dimethyl-3-Phenyl-1,6-Dihydropyridine-2,5-Dione as a Promising Inhibitor of the SARS-CoV-2 Proteins: insight into the Crystal Structure, Hirshfeld Surface Analysis and Computational Study

In this work detailed studies of 1-hydroxy-6,6-dimethyl-3-phenyl-1,6-dihydropyridine-2,5-dione (1), which is of potential biological interest, are reported. The molecule of 1 is stabilized by O–H···O and two C–H···O hydrogen bonds. The former interaction yields a pseudo-aromatic hydrogen bonded five-membered ring. The overall crystal packing of 1 is mainly described by O–H···O hydrogen bonds and π···π interactions, yielding a 1D supramolecular ribbon-like chain. These chains are linked through weak C–H···O hydrogen bonds. The reciprocal favored intermolecular H···H/C/O and C···C contacts are main contributors to the total Hirshfeld surface of 1. The structure, electronic and optical properties of 1 were verified with the DFT calculations, which revealed that 1 is a strong electrophile with the most pronounced nucleophilic and electrophilic centers located on the carbonyl oxygen atoms and on the hydroxyl hydrogen atom, respectively. Values for the calculated polarizability and first-order hyperpolarizability parameters for a molecule of 1 are higher in comparison to those of urea. Bioavailability, druggability as well as absorption, distribution, metabolism, excretion and toxicity properties of 1 were evaluated using the SwissADME, BOILED-Egg and ProTox-II tools. It was established that for 1, the human blood-brain barrier penetration property is positive and gastrointestinal absorption property is high with the negative PGP effect on the molecule. Molecular docking was applied to examine the influence of this compound on a series of the SARS-CoV-2 proteins, of which 1 exhibits the best affinity behavior toward RdRp-RNA, nonstructural protein 14 (N7-MTase) and N protein (NCB site).

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