Synthesis and Antinociceptive Effect of Some Thiazole-Piperazine Derivatives: Involvement of Opioidergic System in the Activity

Abstract

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a–3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a–3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.

Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity

“…Piperazine and thiazole rings are found in a large number of pharmacologically active molecules [16,17,[20][21][22][23][24][25][26][27]. Small molecules containing the thiazole moiety have been demonstrated to possess drug-like properties against a variety of diseases, resulting in, so far, 17 FDA-approved drugs containing the thiazole ring.…”

Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery II

“…Yucel et al designed and synthesized novel molecules with thiazole and piperazine moieties [ 11 ], based on the rationale that many analgesic drugs, such as for example amoxapine and meloxicam, carry these structural motifs. Multiple synthesized molecules produced antinociception in mouse models of acute nociceptive (tail-clip and hot-plate tests) and visceral pain (acetic acid-induced writhing test) following oral administration.…”

“…The availability of high-resolution crystal structures of all opioid receptors in active and inactive conformations offer a unique prospect for drug discovery, and has been a significant development for opioid research [ 25 ]. Multiple articles in this issue [ 4 , 10 , 11 , 26 ] utilized the power of computational techniques (molecular modeling and molecular dynamics simulations) to explore binding mechanisms of peptides and synthetic molecules under investigation using the crystal structures of the opioid receptors. The study by Yucel et al provides an example of a phenotypic screen where molecular docking aided the investigation into the mechanism of action of the molecules bearing thiazole and piperazine moieties in producing opioid receptor-mediated antinociception [ 11 ].…”