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

Laila M Break; Adil A Gobouri; Wafa S Al-Hsrthi; Mohamed Hagar; Nadia S Al-Kaff; Musa A Said

doi:10.55730/1300-0527.3483

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

Turk J Chem. 2022 Jun 16;46(6):1827-1840. doi: 10.55730/1300-0527.3483. eCollection 2022.

Authors

Laila M Break¹, Adil A Gobouri¹, Wafa S Al-Hsrthi¹, Mohamed Hagar², Nadia S Al-Kaff³, Musa A Said^{4

5}

Affiliations

¹ Department of Chemistry, College of Science, Taif University, Taif, Saudi Arabia.
² Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt.
³ Biology Department, College of Science, Taibah University, Al-Madinah Al-Munawara, Saudi Arabia.
⁴ Chemistry Department, College of Science, Taibah University, Al-Madinah Al-Munawara, Saudi Arabia.
⁵ Institute of Inorganic Chemistry, University of Stuttgart Pfaffenwaldring, Stuttgart, Germany.

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 [M^pro, 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.

Keywords: 6,7-difluoro-2-Methyl-4-quinazolinone; Alzheimer’s disease (AD); MD-DFT assessment; Main protease; in silico.

Grants and funding

This research was funded by Researchers Supporting project Taif, Kingdom of Saudi Arabia (KSA, grant number TURSP-2020/137).