Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease

Abstract

Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H₃ receptor ligands (H₃R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a K_i value of 0.012 μM. The multitargeting potential of these H₃R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a K_i value of 0.036 μM at H₃R and IC₅₀ values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

Graphical abstract

Keywords:

• Multitarget-directed ligands
• Alzheimer’s disease
• cholinesterase inhibitors
• histamine H₃ receptor ligands
• monoamine oxidase inhibitors
• benzothiazole derivatives

Acknowledgement

Thanks to Assoc. Prof. Dr. Marek Bajda, Jagiellonian University Medical College in Cracow, Faculty of Pharmacy, Department of Physicochemical Drug Analysis for providing us with the homology model of H₃R to be able to perform the docking studies. Partial support by the EU COST project CA15135 is acknowledged (to HS). Also funding by Ministry of Science and Technology, Taiwan, Chang Gung Memorial Hospital, Taiwan is acknowledged.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Funding by Ministry of Science and Technology, Taiwan [111-2320-B-255-006-MY3] Chang Gung Memorial Hospital, Taiwan [CMRPF1J0051–3, CMRPF1M0131, CORPF1L0011, and BMRP450] is acknowledged.