Antiviral activity of newly synthesized pyrazole derivatives against Newcastle disease virus.

Newcastle disease virus (NDV) is a highly contagious poultry disease that affects the respiratory, nervous, and digestive systems, causing significant losses to the poultry industry. Pyrazole-based scaffolds had significant potential as antiviral agents targeting various pathogens. Thus, a series of 4-substituted pyrazole derivatives were synthesized by reacting 5-chloro-4-formyl-3-methyl-1-phenylpyrazole with some nitrogen and carbon-based nucleophiles. The antiviral efficacy of these compounds was evaluated against NDV by assessing their ability to inhibit virus-induced haemagglutination. Notably, hydrazone 6 and thiazolidinedione derivative 9 achieved complete (100%) protection against NDV with 0% mortality, while the pyrazolopyrimidine derivative 7 provided 95% protection. Additionally, tetrazine 4 and chalcone 11 conferred 85% and 80% protection, respectively. Molecular docking simulation targeting immune receptor TLR4 protein (PDB ID: 3MU3) revealed that compound 6 achieved the highest docking score, surpassing both the reference drug (amantadine) and the co-crystallized ligand (LP4), primarily through hydrophobic interactions with PHE 46 residue. Compound 9 formed two hydrogen bonds with THR 122 and exhibited hydrophobic interaction with TYR 117, whereas compound 7 interacted hydrophobically with THR 122. Pharmacokinetic modeling using the BOILED-Egg model indicated that some compounds are likely to cross the blood-brain barrier (yellow region), while others remain in the white area. Impressively, the compounds also demonstrated desirable drug-likeness profiles. These findings suggest that the synthesized compounds hold promise as potent antiviral candidates.