Synergistic integration of dihydro-artemisinin with γ-aminobutyric acid results in a more potential anti-depressant.

Three hybrids of dihydro-artemisinin (DHA) with ß-aminopropionic acid, γ-aminobutyric acid, and histamine have been designed and synthesized. The conjugate of DHA with GABA labelled as 5b was confirmed the most active candidate against both Cort- and SNP-induced PC12 cell impairments with EC50 value of 8.04 ± 0.35, and 9.38 ± 0.56 µM, respectively. 5b was clearly highlighted as a good modulator on protein expression of Akt, Bcl-2, and Bax, indicating its functions against programmed cell apoptosis. 5b significantly reversed the Cort-induced excessive calcium influx and release from internal organelles. It was demonstrated the ability to express increased levels of ß-tubulin III and to up-regulate phosphorylation level of cAMP response element-binding protein (CREB), leading to cell differentiation. It can penetrate blood - brain barrier (BBB) with propriate stability. Altogether, these data strongly support that 5b is a potential anti-depressant.

Conjugation of tacrine with genipin derivative not only enhances effects on AChE but also leads to autophagy against Alzheimer's disease.

Seven tacrine/CHR21 conjugates have been designed and synthesized. Compound 8-7 was confirmed as the most active AChE inhibitor with IC50 value of 5.8 ± 1.4 nM, which was 7.72-fold stronger than tacrine. It was also shown as a strong BuChE inhibitor (IC50 value of 3.7 ± 1.3 nM). 8-7 was clearly highlighted not only as an excellent ChEs inhibitor, but also as a good modulator on protein expression of AChE, p53, Bax, Bcl-2, LC3, p62, and ULK, indicating its functions against programmed cell apoptosis and decrease of autophagy. 8-7 significantly reversed the glutamate-induced dysfunctions including excessive calcium influx and release from internal organelles, overproduction of nitric oxide (NO) and Aß high molecular weight oligomer. This compound can penetrate blood-brain barrier (BBB). The in vivo hepatotoxicity assay indicated that 8-7 was much less toxic than tacrine. Altogether, these data strongly support that 8-7 is a potential multitarget-directed ligand (MTDL) for treating Alzheimer's disease (AD).