Design, Synthesis of Novel Pyrido[2,3-d] pyrimidine Derivatives as SARS-CoV-2 Mpro Inhibitors for COVID-19 Therapy

Abstract

Some of the interesting pyrido[2,3-d] pyrimidines (3a, 3b), 4, (5a–d), (6a, b), 7–13, and (15a–c) based on uracil moiety were synthesized efficiently using a conventional method and ultrasonic irradiation. Heterocyclic scaffolds such as pyrido[2,3-d] pyrimidines are vital structural elements in drug discovery. Their interactions with different viral mechanistic pathways will be leveraged in future research to create heterocycle-based antivirals. Therefore, the purpose of this work is to demonstrate the anticipated contribution of heterocyclic scaffolds to the advancement and identification of SARS CoV-2 treatment, The newly synthesized compounds were characterized by spectral data, and screened for their binding activity toward the main protease of COVID-19 utilizing a molecular docking study, according to the outcome of our initial screening and docking study, the produced compounds 3a, 4, 6a, 13, 15b, and 15c achieved an evaluation in vitro using the SARS-CoV-2 Mpro utilizing the main protease assay, the results of the evaluation showed that the hydrazinylpyridopyrimidine 4 (IC<inf>50</inf> value: 10.69 µM) and triazolopyrimidin 15c (IC<inf>50</inf> value 8.723 µM) had the greatest inhibitory effects on SARS-CoV-2 Mpro. Additionally, this study was conducted to assess the inhibitory efficacy of the synthesized compounds 4 and 15c, which show moderate inhibition for the replication of SARS CoV-2. Additional molecular dynamics and docking simulations were performed to prove the binding mechanism of 15c.