Sonochemical synthesis, docking studies and in vitro evaluation of imidazo-1,3-oxazinone derivatives as potential inhibitors of TNF-α

• Published in: Journal of molecular structure 2023-11, Vol.1292, p.136239, Article 136239
• Main Authors: Rao, Gajjela Venkata Nageswara, Taneja, Amit Kumar, Tej, Mandava Bhagya, Sri, Komati Navya, Vijayavardhini, Suryadevara, Dandamudi, Srilaxmi, Chinnamaneni, Satya Vani, Kapavarapu, Ravikumar, Rao, Mandava Venkata Basaveswara, Pal, Manojit
• Format: Article
• Language: English
• Subjects: Catalysis; Imidazo-1,3-oxazinone; In silico studies; TNF-α; Ultrasound
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2023.136239

A series of imidazo-1,3-oxazinone derivatives was explored as new and prospective inhibitors of TNF-α. These compounds were synthesized via a direct, one-pot method involving the coupling of appropriate bromo compound with various terminal alkynes in the presence of (PPh3)4Pd, CuI and ZnCl2 in DMF under ultrasound. This sonochemical reaction proceeded via the sequential formation of CC (coupling) and then intramolecular CO bond (cyclization) in the same pot affording the imidazo-1,3-oxazinone derivatives in good yield. A thorough docking studies carried out using the TNF-α protein (PDB: 7JRA and 6 × 81) in silico primarily with the help of AutoDock and then JAMDA docking tool predicted 3j, 3l, 3m and 3o as potential hit molecules from the current series of compounds synthesized. The majority of the compounds interacted with the common interacting residues in the TNF-α trimer e.g. TYR135, TYR227, ILE231, LEU133, LEU233, LEU196 in case of 7JRA and TYR119, TYR59, LEU57, GLY121 in case of 6 × 81. When examined in vitro against TNF-α, the compound 3l, 3m and 3o (with 69–82% inhibition) emerged as the most active compounds in this series. It was observed that the compounds possessing the tricyclic fused ring generally showed better inhibition than that having the fused bicyclic ring as noted during the docking studies. From the viewpoint of SAR (Structure Activity Relationship) the effectiveness of the C-3 aryl group in case of benzoimidazo-1,3-oxazinones was found to be in the order C6H5 > C6H4Me-p > 2-pyridyl > C6H4OMe-p > C6H4Cl-p etc. In terms of IC50 values the compound 3l, 3m and 3o (IC50 ∼5.2–6.2 µM) did not show better activities than rolipram (IC50 ∼0.9 µM) but they appeared to be superior than thalidomide (IC50 ∼197.3 µM). Thus the outcome of docking studies, in vitro evaluation and in silico ADME predictions indicated further pharmacological interest of the preliminary hits identified. [Display omitted]