Can Piperazine-Bearing Fluoro-Benzoxazolone Derivatives Be a Chronotherapeutic Solution for Pain Management?

Objective: Chronic pain management remains limited due to the restricted efficacy and adverse effects of conventional analgesics. A chronotherapeutic approach targeting melatonin MT1 and MT2 receptors offers an alternative solution, as these receptors play a role in the modulation of circadian rhythms and pain. This study aimed to develop piperazine-bearing fluoro-benzoxazolone derivatives with improved binding affinity and pharmacokinetic properties compared to melatonin for MT1 and MT2 receptors. Methods: Four piperazine-bearing fluoro-benzoxazolone derivatives (Compound 1–4) were synthesized via the Mannich reaction. Binding affinities were assessed using molecular docking and molecular mechanics/Poisson–Boltzmann surface area calculations, with melatonin as the reference. Key pharmacokinetic properties were predicted using ADMETLab 3.0. Results: Compound 2 demonstrated the highest binding affinity and stability among the four synthesized compounds. The high affinity and stability indicated enhanced interactions with target receptors compared to melatonin. All synthesized compounds exhibited improved pharmacokinetic profiles relative to melatonin. Conclusion: The synthesized 5-fluoro-benzoxazolone derivatives exhibited promising binding affinities and pharmacokinetic profiles, highlighting their potential as alternative analgesic agents for MT1 and MT2 receptors in chronotherapy applications.