SARS-CoV-2 Mpro binding profile and drug-likeness of two novel thiazole derivatives: structural elucidation, DFT studies, ADME-T and molecular docking simulations

Two novel thiazole derivatives, ethyl 5-((4-fluorophenyl)carbamoyl)-thiazole-4-carboxylate (2b) and ethyl 5-(p-tolylcarbamoyl)thiazole-4-carboxylate (6b) have been synthesized, and their crystal structures determined by X-ray diffraction. To rationalize their structure, reactivity and druggability, we have performed a series of separate, but complementary studies. Hirshfeld surface and 2D-fingerprint plots were first scrutinized to qualitatively unveil all the intermolecular interactions that ensure their crystal packing. Moreover, topological electron density parameters established from the quantum theory of atoms-in-molecules (QTAIM) and Reduced Density Gradient (RDG) were later relied on to characterize the chemical bonding of these species, in terms of the nature and magnitude of noncovalent interactions developed within their monomeric and dimeric forms. In both structures, C-H horizontal ellipsis O hydrogen bonds are found to be stronger than other noncovalent interactions. Furthermore, H horizontal ellipsis H bonding contacts and non-conventional C-H horizontal ellipsis O hydrogen bonds both exhibit a closed shell nature, and play in crucial role in the stability of the novel thiazoles. The isosurfaces in the intermolecular region furnished by NCI molecular diagram signifies the existence of weak noncovalent interactions. Finally, the potential inhibitory activity of the titled compounds and their drug-likeness are demonstrated by molecular docking and ADME-T calculations respectively. Both compounds adhere to the Lipinski's rule of five and present encouraging pharmacokinetic properties and safety profiles.Communicated by Ramaswamy H. Sarma