Synthesis, biological evaluation and molecular docking of 2-(3-alkyl/aryl-2-thioxo-1,3,5-thiadiazinan-5-yl)carboxylic acids as a new class of anti-nociceptive and anti-inflammatory agents

A series of the new 4-methyl-2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl)pentanoic acids (a) and 2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acids (b) were synthesized by reacting primary alkyl/aryl amines with CS 2 , followed by reaction with formaldehyde and aminoacids. Structures of synthesized compounds were confirmed through 13 C- NMR and 1 H- NMR spectra and also their molecular mass was determined. To predict the binding mode of these compounds with COX-1, COX-2, and 5-LOX, docking study was performed. Furthermore, in vitro COX-2 and 5-LOX inhibition assays were carried out. Moreover, anti-nociceptive and anti-inflammatory activities were evaluated in in-vivo thermal induced nociceptive and carrageenan induced paw edema models in mice. The finding of the computational study shows that the tested compounds have binding affinities for COX-1, COX-2, and 5-LOX enzymes, which leads to inhibition of these enzymes. The results of the in vitro study revealed that the tested compounds exhibited concentration dependent COX-2 and 5-LOX inhibition property. The tested compounds at dose of 50 mg/kg have a significant effect on thermally induced pain, reduced latency time (seconds) compared to the vehicle treated animals. Also, tested compounds exhibited percent inhibition of paw edema in the carrageenan induced paw edema model in mice.