Ligand-based design, synthesis, computational insights, and <i>in vitro</i> studies of novel <i>N</i>-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease
Creators: name: Elagawany, Mohamed
name: Elmaaty, Ayman Abo
name: Mostafa, Ahmed
name: Shama, Noura M. Abo
name: Santali, Eman Y.
name: Elgendy, Bahaa
name: Al-Karmalawy, Ahmed A.
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biochemistry
subject: Medicine
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: 60506 Virology

description: The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of <i>N</i>-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle of the SARS-CoV Mpro co-crystallized WR1 inhibitor. Notably, compound <b>3b</b> achieved the most promising anti-SARS-CoV-2 activity with an IC<sub>50</sub> value of 174.7 µg/mL. On the other hand, compounds <b>3a</b>, <b>3b</b>, and <b>3c</b> showed very promising SARS-CoV-2 Mpro inhibitory effects with IC<sub>50</sub> values of 4.67, 5.12, and 11.90 µg/mL, respectively. Compound <b>3b</b> docking score was very promising (−6.94 kcal/mol) and its binding mode was nearly similar to that of WR1. Besides, the molecular dynamics (MD) simulations of compound <b>3b</b> showed its great stability inside the binding pocket until around 40 ns. Finally, a very promising SAR was concluded to help to design more powerful SARS-CoV-2 Mpro inhibitors shortly. HIGHLIGHTSA new series of <i>N</i>-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle.<i>In vitro</i> antiviral activities against SARS-CoV-2 using SARS-CoV-2 cell-based inhibitory assay.The anticipated inhibitory effects of the synthesised compounds (<b>3a–g</b>) towards the SARS-CoV-2 Mpro enzyme were emphasised by using the SARS-CoV-2 Mpro assay.Molecular docking studies, molecular dynamics simulations for 100 ns, and MM-GBSA calculations were carried out for the newly synthesised compounds (<b>3a–g</b>) compared to the co-crystallized inhibitor (WR1).ADMET and toxicity <i>in silico</i> studies were applied for the designed derivatives.Finally, our interesting work rationale helped to conclude a very promising structure-activity relationship (SAR) finding. A new series of <i>N</i>-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle. <i>In vitro</i> antiviral activities against SARS-CoV-2 using SARS-CoV-2 cell-based inhibitory assay. The anticipated inhibitory effects of the synthesised compounds (<b>3a–g</b>) towards the SARS-CoV-2 Mpro enzyme were emphasised by using the SARS-CoV-2 Mpro assay. Molecular docking studies, molecular dynamics simulations for 100 ns, and MM-GBSA calculations were carried out for the newly synthesised compounds (<b>3a–g</b>) compared to the co-crystallized inhibitor (WR1). ADMET and toxicity <i>in silico</i> studies were applied for the designed derivatives. Finally, our interesting work rationale helped to conclude a very promising structure-activity relationship (SAR) finding.