Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents

Abstract

The multifaceted nature of Alzheimer’s disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 μM for AChE and an IC50 value of 1.17 ± 0.09 μM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.

Physical Activity Protects the Pathological Alterations of Alzheimer’s Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways

“…Pathological Aβ accumulation in the kidneys (Gronewold et al, 2017) may result in filtration disorder. Although various signaling molecules have been identified as possible targets in the treatment of this neurodegeneration process (Loera-Valencia et al, 2019;Patel et al, 2019), the complexity of AD makes drug development difficult. Limited data show the importance of physical activity in postponing the manifestation of characteristic AD (Radak et al, 2010;Abraham et al, 2019).…”

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

“…In the search for ChE inhibitors with additional neuroprotective and antioxidant properties, Patel et al reproposed the exploitation of the indole ring to build up novel multiactive structures, guided by the observation that melatonin, based on the same indole moiety, is endowed with free radical scavenging ability and neuroprotection against A β -induced toxicity [ 107 ]. They merged this ring with the 1,2,4-triazine scaffold, which is also a common feature for several drugs, and then explored the effects of thio- and amino-linked aryl/benzyl/aminoalkyl side chains (typified by 42 , Figure 14 ).…”

Design, Synthesis, and Biological Evaluation of 1,2,3-Triazole-linked triazino[5,6-b]indole-benzene sulfonamide Conjugates as Potent Carbonic Anhydrase I, II, IX, and XIII Inhibitors

“…The synthesis of 1,2,3-triazole-linked triazino [5,6-b]indole-benzene sulfonamide hybrids (6a-6o) was performed according to the general synthetic scheme illustrated in Scheme 1. The intermediate compounds (4a-o) were synthesized according to previously reported methods [30,31]. The N-alkylated isatins (3a-o) were synthesized from the simple five-substituted isatins (1a-c) by nucleophilic substitution of different alkyl halides (2a-e).…”

“…The progress of the reaction was monitored by using TLC. Upon the completion of the reaction as assessed by TLC, the reaction mixture was poured into ice water, and the precipitated solid was collected, washed with water, and recrystallized from ethanol to yield compounds (3a-o) (yield 72-75%) [31,32] To a stirred solution of N-alkylated isatin (0.450 g, 0.002378 mol) in 40% aqueous 1,4-dioxane (5 mL), thiosemicarbazide (0.260 g, 0.00285 mol) and Cs 2 CO 3 (0.720 g, 0.00285 mol) were added. The resulting solution was refluxed overnight.…”

“…HCl to pH 1-3. The obtained solids were collected washed with water and dried to give yellow-colored solids which were used without any further purification (yield 68-70%) [31,32]. [5,6b]…”