Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents

Abstract

The inadequate clinical efficacy of the present anti-Alzheimer’s disease (AD) drugs and their low impact on the progression of Alzheimer’s disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)­hexyl)-5H-[1,2,4]­triazino­[5,6-b]­indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 μM; BuChE, IC50 value of 0.21 μM), was also found to possess significant self-mediated Aβ1–42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ1–42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.

Anti‐Epileptic Drug‐Lipid Conjugates for Delivery to the Brain: In Silico ADMET Prediction, Molecular Docking and Molecular Dynamics Simulations

“…It was prepared to ensure structural correctness for hydrogen consistency, bond orders, steric clashes and charges using protein preparation wizard of Maestro. The prepared structure was then used for the generation of grid [42] . The receptor grid was generated using receptor grid generation tool of Maestro by considering the centroid of co‐crystallized ligand HXA (docosahexaenoic acid).…”

“…The molecular docking of nine designed conjugates against HBFABP was performed using extra precision (XP) algorithm of Glide docking module of Maestro. The OPLS3e force field was used in simulations [42] . The conjugates were then ranked based on their docking scores.…”

Novel Coumarin–Pyridine Hybrids as Potent Multi-Target Directed Ligands Aiming at Symptoms of Alzheimer’s Disease

“…Today, millions of people are afflicted with this disease, and the number is projected to increase in the next few years ( Sang et al, 2018 ). Different factors such as inflammation, reduced acetylcholine (ACh) concentration, β-amyloid (Aβ) plaque formation, τ-protein aggregation, and oxidative stress cause AD, while the main reason is not perfectly understood ( Patel et al, 2020 ). One of the most significant factors is the declined cholinergic activity resulting from ACh degradation by acetylcholinesterase (AChE), which affects memory loss.…”

“…One of the most significant factors is the declined cholinergic activity resulting from ACh degradation by acetylcholinesterase (AChE), which affects memory loss. Conventionally approved drugs are mostly AChE inhibitors, increasing the amount of ACh in the synapses and decelerating the advancement of AD ( Reddy et al, 2017 ; Li et al, 2018 ; Patel et al, 2020 ). Moreover, studies on the structure of AChE have indicated that it has two main sites for binding, including a peripheral anionic site (PAS) and a catalytic anionic site (CAS).…”

SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

“…Among heterocyclic compounds, indoles have been investigated extensively due to their interesting versatility [ 23 ] . Many natural and synthetic derivatives of indoles have indeed shown a wide spectrum of pharmacological properties including antibacterial [ 24 - 27 ] , antifungal [ 28 , 29 ] , anti-inflammatory [ 30 ] , antihistamine [ 31 ] , anticholinesterase, antioxidant [ 32 ] , anti-diabetic [ 33 ] , antiviral [ 34 ] and anticancer activities [ 35 , 36 ] .…”