Design, synthesis, and greener pasture biological assessment of a novel nucleoside: 1-(α-D-ribofuranosyl)-6,7-difluoro-2-methyl-4-quinazolinone as an inhibitor of COVID-19 and Alzheimer's disease

ABSTRACT

Synthesis of a new fluorinated nucleoside of 6,7-difluoro-2-methyl-4-quinazolinone was described. 2-Amino-4,5-difluorobenzoic acid 1 reacts with (CH3CO)2O followed by ammonia to form (1H)-6,7-difluoro-2-methyl-4-quinazolinone 3a. Ribosylation of a silylated 4 with l-O-acety1-2,3-5-tri-O-benzoyl-α-D-ribofuranose 5 forms a protected nucleoside 6 then unprotected from 6 to give a free nucleoside 7. Greener pasture biological docking of the cystine protease of COVID-19 [Mpro, code 7BQY, PDB] by novel nucleoside and fluoroquinazoline compounds is presented. LIGPLOT (2D) representations calculated for the same ligands are shown. A superposition of remdesivir approved medicine, N3 inhibitor, and our ligands docked together into the binding protein of 7BQY is also given for a fair comparison. The binding affinities of remdesivir, N3 inhibitor, the nucleoside 7, and fluoroquinazoline 3a, 3b compounds with 7BQY calculated under the same conditions are –7.7, –7.4, –7.6, –6.1, and –6.1 kcal mol–1, respectively. The high values were due to the existence of many hydrophobic interactions and hydrogen bonds between the ligands and the active amino acid residues of the receptor, indicating a promising candidate as a COVID-19 inhibitor. Pro Tox -II server showed that compound 7 has a similar feature to the approved antiviral drug remdesivir for COVID-19. Additionally, a fascinating molecular modeling investigation showed that our nucleoside demonstrated good binding inhibition of AChE enzyme towards advancing an efficient medication against Alzheimer's disease. Finally, DFT has been conducted to illustrate the MD results in terms of the molecular descriptor-based structural activity relationship calculated from FMOs. © TÜBÍTAK.