A number of psychiatric disorders, including anxiety, schizophrenia, Parkinson's disease, depression and others CNS diseases are known to induce defects in the function of neural pathways sustained by the neurotransmitters, like dopamine and serotonin. N-arylpiperazine moiety is important for CNS-activity, particularly for serotonergic and dopaminergic activity. In the scientific literature there are many examples of coumarin-piperazine derivatives, particularly with arylpiperazines linked to a coumarin system via an alkyl liner, which can modulate serotonin, dopamine and adrenergic receptors. Numerous studies have revealed that the inclusion of a piperazine moiety could occasionally provide unexpected improvements in the bioactivity of various biologically active compounds. The piperazine analogs have been shown to have a potent antimicrobial activity and they can also act as BACE-1 inhibitors. On the other hand, arylpiperazines linked to coumarin derivatives have been shown to have antiproliferative activity against leukemia, lung, colon, breast, and prostate tumors. Recently, it has been reported that coumarin-piperazine derivatives exhibit a Fneuroprotective effect by their antioxidant and anti-inflammatory activities and they also show activity as acetylcholinesterase inhibitors and antifilarial activity. In this work we provide a summary of the latest advances in coumarin-related chemistry relevant for biological activity.

A series of new ursolic acid (UA) derivatives substituted with various amino acids (AAs) or dipeptides (DP) at the C-3 position of the steroid skeleton was designed and synthesized. The compounds were obtained by the esterification of UA with the corresponding AAs. The cytotoxic activity of the synthesized conjugates was determined using the hormone-dependent breast cancer cell line MCF-7 and the triple-negative breast cancer cell line MDA. Three derivatives (l-seryloxy-, l-prolyloxy- and l-alanyl-l-isoleucyloxy-) showed micromolar IC₅₀ values and reduced the concentrations of matrix metalloproteinases 2 and 9. Further studies revealed that for two compounds (l-seryloxy- and l-alanyl-l-isoleucyloxy-), a possible mechanism of their antiproliferative action is the activation of caspase-7 and the proapoptotic Bax protein in the apoptotic pathway. The third compound (l-prolyloxy- derivative) showed a different mechanism of action as it induced autophagy as measured by an increase in the concentrations of three autophagy markers: LC3A, LC3B, and beclin-1. This derivative also showed statistically significant inhibition of the proinflammatory cytokines TNF-α and IL-6. Finally, for all synthesized compounds, we computationally predicted their ADME properties as well as performed molecular docking to the estrogen receptor to assess their potential for further development as anticancer agents.

A screening of 18 compounds identified five coumarin derivatives with subnanomolar activity against the 5HT _1A receptor.