Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones

Abstract

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are two attractive targets in the discovery of novel substances that could control multiple aspects of Alzheimer’s disease (AD). Chalcones are the flavonoid derivatives with diverse bioactivities, including AChE and BACE-1 inhibition. In this study, a series of N-substituted-4-phenothiazine-chalcones was synthesized and tested for AChE and BACE-1 inhibitory activities. In silico models, including two-dimensional quantitative structure–activity relationship (2D-QSAR) for AChE and BACE-1 inhibitors, and molecular docking investigation, were developed to elucidate the experimental process. The results indicated that 13 chalcone derivatives were synthesized with relatively high yields (39–81%). The bioactivities of these substances were examined with pIC50 3.73–5.96 (AChE) and 5.20–6.81 (BACE-1). Eleven of synthesized chalcones had completely new structures. Two substances AC4 and AC12 exhibited the highest biological activities on both AChE and BACE-1. These substances could be employed for further researches. In addition to this, the present study results suggested that, by using a combination of two types of predictive models, 2D-QSAR and molecular docking, it was possible to estimate the biological activities of the prepared compounds with relatively high accuracy.

Characterization and Mechanism of Linearized-Microcystinase Involved in Bacterial Degradation of Microcystins

“…They are regarded as the main forces acting as small ligands binding to receptors. Moreover, the combination of 2D and 3D models help to predict the biological activities of the proteins more accurately ( Tran et al, 2020 ).…”

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

“…Kashyap et al observed that two plant natural compounds, reserpine and ajmalicine (Figure 7), also interacted with some of the most rele- Similar to what occurs for synthetic compounds, flavone derivatives (PDB#6EQM), specifically baicalein and diosmetin derivatives [57], 2-phenylbenzimidazoles (PDB#1FKN) [58], 7,8-dihydroxyflavone derivatives (PDB#2ZHS) [59], molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles (PDB#2ZJM), especially compound 4 [60], and quinazolinonebased hydrazones (PDB#4B70) [61], also have demonstrated very promising in silico results that can result in novel drug candidates for BACE-1 inhibition, as shown in (Figure 8). Tran et al [62] built a 2D-QSAR model (R 2 of 0.83) based on the structure of BACE-1 inhibitors found in the literature to identify novel potential inhibitors in a library of chalcone derivatives. The highest-ranking hits were submitted to molecular docking against BACE-1 (PDB#5HU1) to select the most promising candidates [62].…”

“…Tran et al [62] built a 2D-QSAR model (R 2 of 0.83) based on the structure of BACE-1 inhibitors found in the literature to identify novel potential inhibitors in a library of chalcone derivatives. The highest-ranking hits were submitted to molecular docking against BACE-1 (PDB#5HU1) to select the most promising candidates [62]. In particular, compound AC4 (Figure 8), a phenotiazine-chalcone derivative, displayed the highest affinity towards the target [62].…”

“…The highest-ranking hits were submitted to molecular docking against BACE-1 (PDB#5HU1) to select the most promising candidates [62]. In particular, compound AC4 (Figure 8), a phenotiazine-chalcone derivative, displayed the highest affinity towards the target [62]. A distinct procedure was carried out by Subramanian and co-workers, using LBDD to construct a predictive model for small BACE-1 inhibitor molecules [63].…”

Design, Synthesis, and Evaluation of Chalcone Derivatives as Multifunctional Agents against Alzheimer's Disease

“…Chalcones have attracted great research interest due to their numerous biological activities, such as antioxidant activity, anti‐inflammatory, antitumor, antimalarial, antimicrobial, analgesic, and neuroprotection activity [38–44] . Recent studies have also indicated that chalcone derivatives can inhibit Aβ aggregation moderately, and display antioxidation [45–48] . All the above showed that chalcone could be regarded as a starting molecule to design multifunctional drugs for curing AD.…”