A series of substituted 3-amino-3-hydroxymethyloxindoles synthesized through a multi-component approach showed anticancer potency. The most potent compound 5m inhibits SJSA-1 proliferation with an IC50 of 3.14 μM. It can also induce time- and dose-dependent apoptosis.

Agonists of M1 muscarinic acetylcholine receptors are promising therapeutic agents for the treatment of Alzheimer's disease (AD). An example of one of these agents is xanomeline, which has been a leading candidate, however induces various unwanted adverse effects. 3‑[3‑(3‑florophenyl‑2‑propyn‑1‑ylthio)‑1,2,5‑thiadiazol-4-yl]-1,2,5,6-tetrahydro‑1‑methylpyridine oxalate (EUK1001), a fluorinated derivative of xanomeline, has been demonstrated to attenuate AD‑like neurodegenerative pathology in presenilin‑deficient mice, which has no β‑amyloid (Aβ) pathology. The present study assessed the effect of EUK1001 on the behavioral performance of the 3xTg‑AD model of AD. EUK1001 treatment decreased cognitive deficits in male and female AD mice in the Morris water maze test and novel object recognition tasks. EUK1001 also decreased Aβ42, however not Aβ40 in the cortex and hippocampus of AD mice. EUK1001 may also alter amyloid precursor protein processing to a nonamyloidgenic pathway in vitro. These results demonstrate that EUK1001 may ameliorate the cognitive dysfunction of AD mice, possibly by reducing Aβ production. Therefore, EUK1001 may be an effective treatment for AD.

A highly diasetereoselective Mannich-type multicomponent reaction was developed to rapidly construct alkynylamide-substituted α,β-diamino acid derivatives from simple starting materials under mild conditions in moderate to good yields for hit hunting. Most of the resulting products 4 exhibited good anticancer activity in HCT116, BEL7402, and SMMC7721 cells.

Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an effective target for the treatment of both type II diabetes and obesity. However, no PTP1B inhibitor has come into clinic application. Herein, we report mixed 3,3'-bisindoles as novel PTP1B inhibitors with low micromole-ranged inhibitory activity. The best active compound 9f inhibited PTP1B activity with an IC of 2.79 µM. Meanwhile, it had low cytotoxicity and enhanced glucose uptake in vitro. Further studies demonstrated that some of these active compounds had a specific selectivity over other PTPs. Computational analysis further showed the binding mode of compound 9f with the active pocket of PTP1B. Our studies provide a novel scaffold for further development of more promising PTP1B inhibitors and potential drugs for type II diabetes and obesity.