Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents

Abstract

Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.

Dihydropyrimidine-Thiones and Clioquinol Synergize To Target β-Amyloid Cellular Pathologies through a Metal-Dependent Mechanism

“…38 More recently, a multifunctional pyrimidinylthiourea with both inhibitory acetylcholine esterase activity and metal-binding potential were effective in vitro and in vivo. 39 …”

“…Of particular relevance to the current study, a pyrimidinylthiourea inhibited acetylcholinesterase, along with exhibiting activity against multiple A β -metal-dependent phenomena. 39 All activities of this scaffold were enhanced by the thiourea moiety inherent to the inhibitory ACh esterase pharmacophore.…”

Targeting virulence factors as an antimicrobial approach: Pigment inhibitors

“…Our group has been involved in the “drug repurposing” strategy since 2010. During these years, we have not only established and complemented the “old drug bank” (containing over 1500 FDA‐approved drugs) but also repurposed many drugs in various domains, such as the treatment of cancer and Alzheimer's disease . In summary, the “drug repurposing” approach was validated and correlates to the severe situation of the discovery of novel antibacterial agents, which depends on it to transform the resistant crisis to a certain extent.…”

Design, synthesis and evaluation of scutellarein- O -acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease

“…42 aggregation. The screening data showed that the 5-hydroxy at flavonoid nucleus (T-17~T-24) showed remarkably higher inhibitory activity than that of 5-methoxyl(T-3, T-4, T-7, T-8, T-11, T-12, T-15 and T-16), and different tertiary amine units on the side chain had little influence on the inhibitory activity.…”

“…The detection method was the same as above.4.2.9. Studies of cytotoxic effects on SH-SY5Y (MTT assay)[41,42].The human neuroblastoma SH-SY5Y cells were purchased from the American Type Culture Collection (ATCC). The cell line was maintained in Dulbecco's modified Eagle's medium (DMEM from GIBCO) containing 10% (v/v) fetal bovine serum (FBS, Hyclone), 100 U/ml penicillin, and 100 mg/ml streptomycin (Invitrogen).…”