Novel Insights Into Piperazine‐Oxadiazole Hybrids: Promising Pathway for Antidepressant Development

ABSTRACT Depression is a prevalent and debilitating mental health disorder, driving the urgent need for novel and effective therapeutic agents. Piperazine–oxadiazole hybrids have gained significant attention in antidepressant drug discovery due to their unique structural features, favorable CNS pharmacokinetic profile, and pharmacological potential. This review explores the structural significance and recent advancements in these hybrid molecules, focusing on their designed strategies, synthetic approach, and antidepressant activity, with a particular focus on their interactions with key enzymes such as monoamine oxidase. This review also highlights recent advancements in the development and creation of piperazine derivatives and oxadiazole derivatives as potential antidepressants, focusing on their interactions with various receptors and enzymes . Overall, this work underscores the potential of piperazine–oxadiazole hybrids as a promising avenue for the next generation of antidepressant therapeutics. The structural optimization of both piperazine – oxadiazole hybrids is discussed with the help of electron‐withdrawing and electron‐donating groups. The length and flexibility of linkers between piperazine and oxadiazole can dictate spatial orientation and optimize receptor interaction. The recent advancements in piperazine and oxadiazole derivatives and their hybrids as antidepressants are discussed from 2019 to 2024. However, further research and clinical investigations are warranted to fully harness their therapeutic potential in managing depression.