Design, Microwave-Assisted Synthesis and In Silico Prediction Study of Novel Isoxazole Linked Pyranopyrimidinone Conjugates as New Targets for Searching Potential Anti-SARS-CoV-2 Agents

Abstract

A series of novel naphthopyrano[2,3-d]pyrimidin-11(12H)-one containing isoxazole nucleus 4 was synthesized under microwave irradiation and classical conditions in moderate to excellent yields upon 1,3-dipolar cycloaddition reaction using various arylnitrile oxides under copper(I) catalyst. A one-pot, three-component reaction, N-propargylation and Dimroth rearrangement were used as the key steps for the preparation of the dipolarophiles3. The structures of the synthesized compounds were established by 1H NMR, 13C NMR and HRMS-ES means. The present study aims to also predict the theoretical assembly of the COVID-19 protease (SARS-CoV-2 Mpro) and to discover in advance whether this protein can be targeted by the compounds 4a–1 and thus be synthesized. The docking scores of these compounds were compared to those of the co-crystallized native ligand inhibitor (N3) which was used as a reference standard. The results showed that all the synthesized compounds (4a–l) gave interesting binding scores compared to those of N3 inhibitor. It was found that compounds 4a, 4e and 4i achieved greatly similar binding scores and modes of interaction than N3, indicating promising affinity towards SARS-CoV-2 Mpro. On the other hand, the derivatives 4k, 4h and 4j showed binding energy scores (−8.9, −8.5 and −8.4 kcal/mol, respectively) higher than the Mpro N3 inhibitor (−7.0 kcal/mol), revealing, in their turn, a strong interaction with the target protease, although their interactions were not entirely comparable to that of the reference N3.

Synthesis of bis-furyl-pyrrolo[3,4-b]pyridin-5-ones via Ugi–Zhu reaction and in vitro activity assays against human SARS-CoV-2 and in silico studies on its main proteins

“…Several compounds bearing pyrimidine, isoxazole, as well as pyranyl–pyrimidinone moieties have been synthesized and evaluated through in silico models against SARS-CoV-2, showing promising results. 30 These previous works motivated us to synthesize the pyrrolo[3,4- b ]pyridin-5-ones that are herein reported. Striking results were obtained after the in vitro evaluation against SARS-CoV-2 as we find that five out of the six compounds demonstrated potential to inhibit the SARS-CoV-2 infection.…”

Recent advancements in the multicomponent synthesis of heterocycles integrated with a pyrano[2,3-d]pyrimidine core

“…In another route, Algethami et al 129 have progressed to the synthesis of naphthopyranopyrimidinones 58 through a three-step approach. In this route, heating of naphthopyrans 56 with acetic anhydride containing phosphoric acid, subsequently treatment with sodium hydride, and 3-bromoprop-1-yne gave the corresponding N -propargylated naphtha-pyranopyrimidines 57.…”

Insights into the recent progress in the medicinal chemistry of pyranopyrimidine analogs

“…85 The scope of the research was extended for in silico studies to predict the potency of pyranopyrimidinonederived isoxazole conjugates as potential antiSARS-CoV-2 agents. 86 Shamroukh et al 42…”

“…85 The scope of the research was extended for in silico studies to predict the potency of pyranopyrimidinone-derived isoxazole conjugates as potential antiSARS-CoV-2 agents. 86 Shamroukh et al 42 designed the synthesis of a series including binary and tricyclic pyranopyrimidines 100–113 , as shown in Scheme 26. The protocol involved the utility of 5-cyano-6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3- c ]pyrazole 99 to synthesize the desired tricyclic pyrazolopyranopyrimidines 100–102 through multi-step synthesis involving the reaction with acetic anhydride, treatment with ammonium hydroxide, and next treatment with phosphorus oxychloride.…”