Structural understanding of 5-(4-hydroxy-phenyl)-N-(2-(5-methoxy-1H-indol-3-yl)-ethyl)-3-oxopentanamide as a neuroprotectant for Alzheimer's disease.

In our continuing efforts to develop novel neuroprotectants for Alzheimer's disease (AD), a series of analogs based on a lead compound that was recently shown to target the mitochondrial complex I were designed, synthesized and biologically characterized to understand the structure features that are important for neuroprotective activities. The results from a cellular AD model highlighted the important roles of the 4-OH on the phenyl ring and the 5-OCH3 on the indole ring of the lead compound. The results also demonstrated that the ß-keto moiety can be modified to retain or improve the neuroprotective activity. Docking studies of selected analogs to the FMN site of mitochondrial complex I also supported the observed neuroprotective activities. Collectively, the results provide further information to guide optimization and development of analogs based on this chemical scaffold as neuroprotectants with a novel mechanism of action for AD.

Characterization and Discovery of a Selective Small-Molecule Modulator of Mitochondrial Complex I Targeting a Unique Binding Site.

Mitochondrial dysfunction has been recognized as an essential contributor to many human diseases including neurodegenerative disorders. However, the exact pathological role of mitochondrial dysfunction, especially in mitochondrial reactive oxygen species-associated oxidative stress, remains elusive, partially due to the lack of chemical probes with well-defined mechanisms of action. Herein, we describe the characterization and discovery of a rationally designed small molecule ZCM-I-1 as a selective modulator of the production of reactive oxygen species from mitochondrial complex I that does not alter mitochondrial membrane potential and bioenergetics. Chemical biology studies employing photoaffinity probes derived from ZCM-I-1 demonstrated its novel mechanism of action of modulating complex I via interactions with the flavin mononucleotide site, proximal in the reaction pathway within complex I.

Discovery of Second-Generation NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

NLRP3 inflammasomes have recently emerged as an attractive drug target for neurodegenerative disorders. In our continuing studies, a new chemical scaffold was designed as selective inhibitors of NLRP3 inflammasomes. Initial characterization of the lead HL16 demonstrated improved, however, nonselective inhibition on the NLRP3 inflammasome. Structure-activity relationship studies of HL16 identified a new lead, 17 (YQ128), with an IC50 of 0.30 ± 0.01 µM. Further studies from in vitro and in vivo models confirmed its selective inhibition on the NLRP3 inflammasome and its brain penetration. Furthermore, pharmacokinetic studies in rats at 20 mg/kg indicated extensive systemic clearance and tissue distribution, leading to a half-life of 6.6 h. However, the oral bioavailability is estimated to be only 10%, which may reflect limited GI permeability and possibly high first-pass effects. Collectively, these findings strongly encourage development of more potent analogues with improved pharmacokinetic properties from this new chemical scaffold.

Development of bivalent compounds as potential neuroprotectants for Alzheimer's disease.

In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC50 of 81.86 ±â€¯11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer's disease.