Design, synthesis, in-vitro biological screening and in-silico studies of 2-thioxodihydropyrimidinone based new aminomethylene scaffolds

A successful attempt was made to avail ten new 5-anilinoaminomethylene substituted 2-thioxodihydropyrimidinones (H1-H10) via one-pot three-component reaction of 1,3-diethyl-2-thiobarbituric acid, triethyl orthoformate and respective substituted anilines in good to excellent yields (84-92 %). All the synthesized compounds were fully characterized by detailed spectroscopic techniques, like UV-Vis., IR, NMR and HRMS after purification. In-vitro investigations including DPPH free radical scavenging ability, acetyl- and butyrylcholinesterases inhibition, alpha-glucosidase inhibition, phytotoxicity and insecticidal activities of the synthesized compounds were performed, and very promising results were obtained. Compounds H6-H10 showed amazing potency as DPPH free radical scavengers with IC50 values of 0.88 +/- 0.053, 0.54 +/- 0.164, 1.22 +/- 0.07, 0.20 +/- 0.055 and 1.58 +/- 0.123 mg/mL, respectively, better than reference compound ascorbic acid (IC50 1.79 +/- 0.045 mg/mL). Similarly, compounds H2 and H4 declared greater inhibition of alpha-glucosidase enzyme with IC50 of 319.46 +/- 1.45 and 263.57 +/- 1.34 mu M respectively, as compared to the reference compound acarbose (IC50 375.82 +/- 1.76 mu M). The bioinformatics study of the synthesized compounds comprised drug likeness, metabolites prediction, molecular docking analyses against eight selected target substrates. Docking analysis showed that the binding energy values of compounds H2, H3 and H5 were -11.25, -10.91 and -12.30 Kcal/mol respectively, which are better than standard drug diltiazem possessing -10.79 Kcal/mol against P450 CYP 3A4. Finally, the rat acute toxicities were estimated through four different routes of administration and the results reflect promising behaviors of the test compounds in their toxicity evaluation. Based on the encouraging results in all these analyses, our target compounds may be used as hits for future investigation towards drug discovery.