Investigation of an aminothiazole-based scaffold as an anti-inflammatory agent: Potential application in the management of cytokine storm in SARS-CoV-19

• Published in: Journal of molecular structure 2024-05, Vol.1303, p.137562, Article 137562
• Main Authors: Ganie, Majid Ahmad, Ansari, Shaghaf Mobin, Choudhary, Rupali, Fayaz, Faheem, Kour, Gurleen, Gupta, Vivek, Ahmed, Zabeer, Javed, Saleem, Shah, Bhahwal Ali
• Format: Article
• Language: English
• Subjects: Aminothiazole; COVID-19; Cytokine storm; Inflammation; Molecular docking
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.137562

•An aminothiazole derivative X22 showed a significant reduction in the levels of inflammatory mediators including NO, TNF-α and IL-6 in RAW 264.7 cells stimulated with LPS.•MEP revealed that the reactive sites are located in CF3 and NH2 groups. These particular groups exhibit a strong propensity to engage in hydrogen bonding and dipole-dipole interactions.•Molecular docking studies revealed that ligand (X22) binds to TNF-α and IL-6 via H-bonding with amino acids, Tyr151, Ser60, Gln61, and Arg179.•MD simulation data demonstrated that TNF-alpha exhibits effective binding to the active sites of proteins, resulting in the formation of a stable protein complex. Aminothiazole-based structures, including compounds like anakinra, nitazoxanide, amiphenazole, and tizoxanide, along with cytokine-blocking agents such as tocilizumab and siltuximab are currently under extensive investigation for their potential in managing severe COVID-19 by specifically targeting and inhibiting cytokines responsible for cytokine release syndrome (CRS). These targeted therapies have shown promising results in effectively mitigating the effects of severe COVID-19. Herein, we carried out a biological assessment of a novel aminothiazole-based derivative 5-(phenylthio)-4-(2-(trifluoromethyl) phenyl) thiazol-2-amine (X22) to gauge its potential as an anti-inflammatory agent. Utilizing in vitro assays, which included measuring nitric oxide (NO) inhibition and observing the production of LPS-induced pro-inflammatory cytokines (TNF-α and IL-6) in RAW 264.7 macrophages. Furthermore, the X22 was characterized by experimental FT-IR, NMR, and UV–visible spectral analysis. The optimized molecular geometry and vibrational wave numbers were calculated using the DFT and B3LYP/6–311++G (d,p) basis set. The vibrational assignments were calculated using VEDA's Potential Energy Distribution (PED) program. 1H and 13C NMR were calculated by the GIAO method. Additionally, compounds HOMO-LUMO and HF interactions were studied. Subsequently, the MEP map was traced to find the reactive sites of X22. In addition, Mulliken population analysis and thermodynamic properties with respect to various temperatures were also calculated. All the theoretical predictions were carried out by using the DFT-B3LYP method at the level of 6–311++G (d,p). Finally, the molecular docking interactions revealed that ligand (X22) binds to TNF-α and IL-6 via H-bonding with amino acids Tyr 151, Ser60, Gln61, and Arg179. These findings sugg