Synthesis, X-ray crystal structure, Hirshfeld surface analysis and computational investigation into the potential inhibitory action of novel 6-(p-tolyl)-2-((p-tolyl)thio)methyl-7H-[1.2.4]triazolo[5,1-b][1,3,4]thiadiazine inhibits the main protease of COVID-19

Abstract

In recent times, the novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become a worldwide pandemic. With over 71 million confirmed cases, even though the effectiveness and side effects of the specific drugs and vaccines approved for this disease are still limited. Scientists and researchers from all across the world are working to find a vaccine and a cure for COVID-19 by using large-scale drug discovery and analysis. Heterocyclic compounds are regarded to be valuable sources for the discovery of new antiviral medications against SARS-CoV-2 because virus occurrences are still on the rise, and infectivity and mortality may also rise shortly. In this regard, we have synthesized a new triazolothiadiazine derivative. The structure was characterized by NMR spectra and confirmed by X-ray diffraction analysis. The structural geometry coordinates of the title compound are well reproduced by DFT calculations. NBO and NPA analyses have been performed to determine the interaction energies between bonding and antibonding orbital, and natural atomic charges of heavy atoms. Molecular docking suggests that the compounds may have good affinity for SAR-CoV-2 main protease, RNA-dependent RNA polymerase and nucleocapsid enzymes, particularly the main protease enzyme (binding energy of −11.9 kcal mol⁻¹). The predicted docked pose of the compound is dynamically stable and reports a major van der Waals contribution (−62.00 kcal mol⁻¹) to overall net energy.

Communicated by Ramaswamy H. Sarma

Keywords:

• Triazolothiadiazine
• COVID-19
• crystal structure
• DFT calculations
• molecular docking
• molecular dynamics simulation

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

Data sharing is not applicable on this article as no data sets were generated or analyzed during the current study.

Scheme 1. The synthesis route of the title compound.

Additional information

Funding

This study is supported via funding from Prince sattam bin Abdulaziz University project number (PSAU/2023/R/1444).