Baichen Xiong's research while affiliated with China Pharmaceutical University and other places

Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory (eeAChE IC50 = 0.07 ± 0.01 μM; hAChE IC50 = 0.38 ± 0.04 μM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H2O2 and Aβ1-42 aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and Aβ1-42. At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.

Tyrosinase is a bifunctional polyphenol oxidase (PPO), catalyzing two oxidative reactions: monophenols to o-quinones (monophenolase activity) and o-diphenols to o-quinones (diphenolase activity). As tyrosinase is the rate-limiting enzyme for the melanogenesis process, it is an attractive target for melanogenesis inhibition. Aiming at skin whitening, anticancer, Parkinson’s disease (PD) treatment, antibacterial, fruit and vegetable preservation and other anti-pigmentation effect, medicinal chemists have exploited diverse tyrosinase inhibitors through various approaches. In addition to discovering inhibitors with novel scaffold, good activity and high safety, researchers also focused on developing strategies for synergistic effects of multiple inhibitors and simultaneously regulating multiple targets to treat cancer or neurodegenerative diseases. This review focused on multiple natural and synthetic tyrosinase inhibitors which could contribute to preventing fruit and vegetable browning, skin whitening, antibacterial, anticancer, Parkinson's Disease etc.

Butyrylcholinesterase (BChE) has been more and more attractive for treating neurodegenerative diseases, especially Alzheimer's disease (AD). In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC50 values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC50 = 2.94 nM, hBChE IC50 = 34.6 nM and 20, eqBChE IC50 = 0.15 nM, hBChE IC50 = 45.2 nM) has been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments. Two candidates exhibited remarkable neuroprotective properties and cognition improving activity, by benefiting cholinergic system, reducing the total Aβ amount and increasing the ghrelin content. Simultaneous modulation in the center and periphery greatly improves the efficiency of BChE inhibitors. Considering the regulation on ghrelin level, BChE inhibition could improve not only symptoms but also nutritional status of AD patients.

In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schrödinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513–4169 displayed the highest inhibitory activity and selectivity against BChE (eeAChE IC50 > 10 μM, eqBChE IC50 = 3.73 ± 1.90 μM). Molecular dynamic (MD) simulation validated the binding pattern of 2513–4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513–4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513–4169 against toxic Aβ1–42. In vivo behavioral study further confirmed the great efficacy of 2513–4169 on reversing Aβ1–42-induced cognitive impairment of mice and clearing the toxic Aβ1–42 in brains. Moreover, 2513–4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513–4169 is a promising lead compound for future optimization to discover anti-AD treating agents.

Structural information of butyrylcholinesterase (BChE) and its variants associated with several diseases are discussed here. Pure human BChE has been proved safe and effective in treating organophosphorus (OPs) poisoning and has completed Phase 1 and 2 pharmacokinetic (PK) and safety studies. The introduction of specific mutations into native BChE to endow it a self‐reactivating property has gained much progress in producing effective OPs hydrolases. The hydrolysis ability of native BChE on cocaine has been confirmed but was blocked to clinical application due to poor PK properties. Several BChE mutants with elevated cocaine hydrolysis activity were published, some of which have shown safety and efficiency in treating cocaine addiction of human. The increased level of BChE in progressed Alzheimer's disease patients made it a promising target to elevate acetylcholine level and attenuate cognitive status. A variety of selective BChE inhibitors with high inhibitory activity published in recent years are reviewed here. BChE could influence the weight and insulin secretion and resistance of BChE knockout (KO) mice through hydrolyzing ghrelin. The BChE‐ghrelin pathway could also regulate aggressive behaviors of BChE‐KO mice.

To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC50 = 0.18 ± 0.03 μM, hBChE IC50 = 0.32 ± 0.07 μM) was purchased and synthesized. It inhibited BChE in a non-competitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proved to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aβ1-42 (icv)-impaired cognitive function to normal level and showed better behavioral performance than donepezil. The evaluation of Aβ1-42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T1/2 and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.