Towards novel tacrine analogues: Pd(dppf)Cl2·CH2Cl2 catalyzed improved synthesis, in silico docking and hepatotoxicity studies

Babu, Aravinda; Joy, Muthipeedika Nibin; Sunil, K.; Sajith, Ayyiliath M.; Santra, Sougata; Zyryanov, Grigory V.; Konovalova, Olga A; Butorin, Ilya I.; Muniraju, Keesaram

doi:10.1039/d2ra03225b

Cited by 6 publications

(4 citation statements)

References 25 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies demonstrated the hepatoprotective properties of 4-phenyltetrahydroquinolines, which were designed based on the structure of tacrine [ 18 , 21 , 22 ]. The appeal of these compounds stems from their diverse structural and biological characteristics [ 48 – 50 ]. In this study, we investigated the toxicity profile and hepatoprotective effects of four novel 4-phenyltetrahydroquinoline derivatives and their potential mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition

Abdelgalil,

Elhammamy,

Ragab

et al. 2024

Biol Res

View full text Add to dashboard Cite

Background The liver serves as a metabolic hub within the human body, playing a crucial role in various essential functions, such as detoxification, nutrient metabolism, and hormone regulation. Therefore, protecting the liver against endogenous and exogenous insults has become a primary focus in medical research. Consequently, the potential hepatoprotective properties of multiple 4-phenyltetrahydroquinolines inspired us to thoroughly study the influence of four specially designed and synthesized derivatives on carbon tetrachloride (CCl4)-induced liver injury in rats. Methods and results Seventy-seven Wistar albino male rats weighing 140 ± 18 g were divided into eleven groups to investigate both the toxicity profile and the hepatoprotective potential of 4-phenyltetrahydroquinolines. An in-vivo hepatotoxicity model was conducted using CCl4 (1 ml/kg body weight, a 1:1 v/v mixture with corn oil, i.p.) every 72 h for 14 days. The concurrent treatment of rats with our newly synthesized compounds (each at a dose of 25 mg/kg body weight, suspended in 0.5% CMC, p.o.) every 24 h effectively lowered transaminases, preserved liver tissue integrity, and mitigated oxidative stress and inflammation. Moreover, the histopathological examination of liver tissues revealed a significant reduction in liver fibrosis, which was further supported by the immunohistochemical analysis of α-SMA. Additionally, the expression of the apoptotic genes BAX and BCL2 was monitored using real-time PCR, which showed a significant decrease in liver apoptosis. Further investigations unveiled the ability of the compounds to significantly decrease the expression of autophagy-related proteins, Beclin-1 and LC3B, consequently inhibiting autophagy. Finally, our computer-assisted simulation dockingonfirmed the obtained experimental activities. Conclusion Our findings suggest that derivatives of 4-phenyltetrahydroquinoline demonstrate hepatoprotective properties in CCl4-induced liver damage and fibrosis in rats. The potential mechanism of action may be due to the inhibition of autophagy in liver cells.

show abstract

Section: Discussionmentioning

confidence: 99%

The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition

Abdelgalil,

Elhammamy,

Ragab

et al. 2024

Biol Res

View full text Add to dashboard Cite

show abstract

“…[33] The Suzuki-Miyaura reaction is an exceptionally appealing method that involves the reaction of halogen-containing tacrines with (hetero)aromatic boronic acids or esters to enhance their bioactivity properties. [34,35] The Suzuki-Miyaura reaction is a cross-coupling reaction that forms C-C bonds between heteroaryl, aryl, alkenyl, or alkynyl organoboranes and organic halides or pseudohalides, catalyzed by a transition metal, often palladium, under basic conditions. [36,37] This coupling reaction is a versatile synthetic strategy for obtaining various bioactive molecules and important compounds across various research fields, thanks to its mild reaction conditions.…”

Section: Introductionmentioning

confidence: 99%

Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities

Mısır,

Derin,

Ökten

et al. 2024

J Biochem & Molecular Tox

View full text Add to dashboard Cite

In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two‐step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a–e and 4a–e using a Suzuki–Miyaura cross‐coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5‐Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer‐specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7‐bis(4‐(methylthio)phenyl)tacrine (3d), 5,7‐bis(4‐(trifluoromethoxy)phenyl)tacrine (3e), 2,4‐bis(4‐(trifluoromethoxy)phenyl)‐7,8,9,10‐tetrahydro‐6H‐cyclohepta[b]quinolin‐11‐amine (4e), and 6,8‐dibromotacrine (3), emerged as the most promising candidates for preclinical studies.

show abstract

“…The molecular docking approach, used to model the interaction between a small molecule and a protein at the atomic level, allowed us to characterize the behavior of small molecules in the binding site of target proteins and to resolve fundamental biochemical processes [ 10 ]. Once the docking results were obtained, it was necessary to determine the structural behavior of the most active molecular characteristics, such as structural orientation, any biological influence in the structure, the parameters that can force the achievement of the biological activity of the molecule, and others [ 11 ]. Then, we performed molecular dynamics simulations to analyze and deepen the details of the interaction and stability of the two docked ligands in the target proteins [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer

Er-rajy

fadili

Imtara

et al. 2023

Life

View full text Add to dashboard Cite

Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave Rpred2 = 0.683, Rpred 2= 0.758, and Rpred 2= 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.

show abstract

Towards novel tacrine analogues: Pd(dppf)Cl₂·CH₂Cl₂ catalyzed improved synthesis, in silico docking and hepatotoxicity studies

Abstract: 24 synthesized compounds by various cross-coupling reactions on 6-bromo tacrine. Molecular docking and toxicity prediction studies were also performed.

Cited by 6 publications

References 25 publications

The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition

The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition

Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities

3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer

Contact Info

Product

Resources

About