Identification of 2-subsituted benzothiazole derivatives as triple-functional agents with potential for AD therapy

Abstract

A series of 2-subsituted benzothiazole derivatives were designed and synthesized as MDTLs for potential AD therapy.

Preparation of Benzothiazolyl-Decorated Nanoliposomes

“…In order to take advantage of the affinity of BTH-groups towards Aβ species [27,28,29,30,31,32,33,34,35,36] and the potential of surface functionalized nanoliposomes for enhanced targeting due to multivalency [14,15,16], we prepared nanoliposomes decorated with BTH. For this, we initially synthesized a lipid-BTH derivative, with high yield, after identifying an optimal methodology.…”

“…Taking into consideration that thioflavin-T (ThT) is the most widely used (in vitro) indicator of Aβ aggregation displaying fluorescence enhancement and a characteristic red shift when binding to Aβ aggregates, the decoration of nanoliposomes with benzothiazoles (BTH), the moiety that is responsible for the affinity of ThT towards Aβ aggregates [24,25,26], may potentially be an improved method for Aβ targeting. In fact, benzothiazoles bearing only the 2-benzothiazolyl-moiety [27,28,29,30], or more complicated 2-benzothiazolyl-derivatives [31,32,33,34,35,36], have been prepared and tested for their affinity towards amyloids, however none of the previous molecules were ever tested after immobilization on nanoliposomes. Additionally, it should be pointed out that the bulky and ionic nature of ThT is a negative parameter for its permeation across the blood–brain barrier (BBB), explaining why no benefits were obtained from this compound in vivo [37,38,39,40].…”

Hydroxypyridinone-Based Iron Chelators with Broad-Ranging Biological Activities

“…These compounds have activities against metal ions, Aβ aggregation, and oxidative stress, showing a good triple effect. 118 Two optimal compounds, 53a and 53b, exhibited excellent anti-Aβ aggregation activity, high ABTS (2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)) radical scavenger activity, strong metal chelation properties, and depolymerization activity against previously formed fibers. In addition, no cytotoxicity was found in human glioma U251 cells at concentrations less than 50 μM.…”

“…Furthermore, the substituents at the C-2 position of pyranone impacted the activity slightly; however, the methyl group in the C-1 position decreased the antioxidant capacities obviously, indicating the detrimental steric effect on antioxidant activity. 118 In general, C-2 and C-6 hydroxyl substituted benzothiazole ring and unsubstituted pyranone were superior.…”

2-(4′-Aminophenyl)benzothiazole Labeled with 99mTc-Cyclopentadienyl for Imaging β-Amyloid Plaques

“…Even though 99m Tc complexes of higher initial uptake have been reported in the literature, the intricate balance of requirements that a new agent should display in order to be considered for application makes this compact and lipophilic complex a promising structural alternative worth of further fine-tuning to meet the prerequisites of a SPECT amyloid imaging agent. Moreover, the diverse pharmacological spectrum of 2-substituted benzothiazoles (including cancer, inflammation, microbes, neurological disorders − ) justifies the further exploration of potential applications of 99m Tc-1 and its rhenium analogue Re-1.…”