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.

Faisal K Algethami,Naoufel Ben Hamadi,Anis Romdhane,Mohamed R Elamin,Maher Cherif,Mashael A Alghamdi,Hichem Ben Jannet,Salma Jlizi

doi:10.3390/molecules26206103

Faisal K Algethami, Naoufel Ben Hamadi + Show 6 more

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https://doi.org/10.3390/molecules26206103

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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.

Highlights

Coronaviruses (CoVs) tend to have a high zoonotic potential and according to theWorld Health Organization (WHO), these viral diseases have emerged as a serious health issue to the world [1]
One of the ways that several research teams are thinking is to highlight promising molecules and drug compounds by making a virtual screening via molecular docking of drugs approved by the FDA, certain natural substances, and synthetic heterocyclic compounds such as pyranopyrimidinones linked
Molecules 2021, 26, 6103 the ways that several research teams are thinking is to highlight promising molecules2 of and drug compounds by making a virtual screening via molecular docking of drugs approved by the FDA, certain natural substances, and synthetic heterocyclic compounds such as pyranopyrimidinones linked to isoxazoles for probable therapeutic outcome.compounds

Summary

Introduction

Coronaviruses (CoVs) tend to have a high zoonotic potential and according to theWorld Health Organization (WHO), these viral diseases have emerged as a serious health issue to the world [1]. The WHO declared a state of global health emergency to coordinate scientific and medical efforts to rapidly develop a cure for patients [2]. The discovery of an antiviral drug is of immense importance in the current spread of the rapidly modifiable SARS-CoV-2. Molecules 2021, 26, 6103 the ways that several research teams are thinking is to highlight promising molecules of and drug compounds by making a virtual screening via molecular docking of drugs approved by the FDA, certain natural substances, and synthetic heterocyclic compounds such as pyranopyrimidinones linked to isoxazoles for probable therapeutic outcome.compounds. In this conto isoxazoles for probable therapeutic outcome.

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