Unveiling the therapeutic potential of prenyl motif-containing derivatives: a key structural fragment for designing antidepressant compounds

Depression is a complex mental disorder, and consequently, the successful treatment of the depressive disorder remains challenging. The available medications often show limitations in terms of both safety and efficacy. In this case, the presence of the prenyl motif in pharmaceutical compounds has resulted in a broad spectrum of biological activities. Various studies have highlighted that the potent antidepressant activity of many natural compounds is associated with the presence of the prenyl motif. Thus, some studies have attempted to prepare prenyl fragment derivatives with the aim of enhancing their hydrophobicity and developing promising antidepressant compounds. Prenyl motif-containing compounds exhibit antidepressant action via multiple mechanisms, including selective serotonin/norepinephrine reuptake inhibition, blocking of NMDA receptors, 5-HT₆ antagonism, TREK-1 inhibition, MAO-A inhibition, and anti-inflammatory and antioxidant properties. This review presents synthetic derivatives of xanthones, flavonoids, and chalcones bearing prenyl groups. It also covers polyprenylated benzoyl phloroglucinols/acylphloroglucinols, naphthoquinones, volatile oils, tricyclic products, and steroidal saponins containing prenyl motifs. This study aims to further guide and support medicinal chemists in directing the synthesis of more potent compounds possessing prenyl fragments as antidepressants, thus advancing treatment options for depression.