Jul 2026· Current Computer - Aided Drug Design· 0 citations
TL;DR
The present study demonstrates that DHPM derivatives, specifically DHPM 22, may represent a promising lead for the development of new antioxidant derivatives, and further experimental studies are recommended to confirm their biological activities and therapeutic potential.
Abstract
Reactive oxygen species and endogenous antioxidants are essential for
normal cellular metabolism; however, an imbalance between them causes oxidative stress,
which significantly contributes to the onset and progression of various diseases, including neurodegenerative,
cancer, and cardiovascular disorders. Thus, designing new antioxidant scaffolds
is an important research priority. Among the many heterocycles, 3,4-dihydropyrimidin-2(1H)-
one (DHPM) derivatives are particularly appealing because of their structural diversity and simple
synthesis route through the Biginelli reaction. This study aimed to identify potent antioxidant
DHPM derivatives using a structure-based computational approach.
The target protein (PDB ID: 4IQK) was prepared and optimised for docking studies.
Standard antioxidant drugs were retrieved from the PubChem database. The generated compounds
were subjected to molecular modeling to evaluate their binding affinities with the target
protein. In addition, the pharmacokinetic and ADME/T properties of the compounds were assessed
using pkCSM.
Among the thirty DHPM derivatives evaluated, six derivatives had strong binding affinities,
with values between -7.9 and -8.0 kcal/mol. Compound DHPM 22 was the most powerful
lead among them. It exhibited a better binding affinity of -8.0 kcal/mol because it formed
hydrogen bonds, π-π stacking, and hydrophobic interactions with the protein's active site. Furthermore,
ADME/T analysis confirmed the favorable drug-likeness and pharmacokinetic properties
of the selected compounds.
The docking and ADME/T studies of the 3,4-dihydropyrimidin-2(1H)-one derivatives
showed favorable antioxidant activity against the Keap protein with PDB ID: 4IQK.
Amongst the designed compounds, compound DHPM 22 showed the highest binding affinity (-
8.0 kcal/mol), which was comparable to the standard 4-bromoflavone (-8.5 kcal/mol). This enhanced
binding affinity can be attributed to the formation of conventional hydrogen bonds with
Gly367A, Val465A, and Gly464A, hydrophobic interactions with Val418A, Ile416A, Ala366A,
Leu557A, Leu365A, Val604A, and Val606A, as well as a π-alkyl interaction with Ile559A, collectively
contributing to the stabilization of the ligand within the active site. Compounds DHPM
3 and DHPM 29 also showed favorable binding scores of -7.9 and -7.8 kcal/mol, respectively.
The structure-activity relationship suggests that the electron-withdrawing groups like fluoro and
bromo enhanced binding affinity, whereas bulky polar substituents reduced the antioxidant activity.
Overall, the present study demonstrates that DHPM derivatives, specifically
DHPM 22, may represent a promising lead for the development of new antioxidant derivatives.
Further experimental studies are recommended to confirm their biological activities and therapeutic
potential.
Structural-activity relationship analysis indicated that the electron-withdrawing substituents at the para-position of aryl ring, together with nitrogen-containing heteroaromatic moieties, improve both binding affinity and free radical scavenging activity.
Nitesh Diyora, N. Parekh· Asian Journal of Chemistry· 0 citations
INTRODUCTION/BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction and excessive oxidative stress. Targeting acetylcholinesterase (AChE) alongside antioxidant mechanisms represents a rational multitarget therapeutic strategy. The present study aimed to design, synthesize, and evaluate a new series of 2-mercaptobenzimidazole derivatives as potential dual-acting anti-Alzheimer agents.
METHODS
A series of eight novel 2-mercaptobenzimidazole derivatives (2a-2h) was synthesized through a two-step synthetic route involving acylation of substituted amines with chloroacetyl chloride, followed by coupling with 2-mercaptobenzimidazole. Structural elucidation was performed using standard spectroscopic techniques. in silico ADMET profiling and molecular docking were conducted against human AChE (PDB ID: 4EY7). The compounds were further evaluated for in vitro AChE inhibitory activity, enzyme kinetics, and antioxidant potential using the DPPH radical scavenging assay.
RESULTS
ADMET analysis predicted favorable drug-like characteristics, including acceptable physicochemical properties, good intestinal absorption, and low hepatotoxicity risk. Molecular docking studies revealed enhanced binding affinity for derivatives bearing electron-withdrawing substituents, with compound 2d demonstrating the strongest interaction (-10.6 kcal/mol) through π-π stacking and hydrogen bonding within the active site. in vitro AChE inhibition assays supported the computational findings, where compounds 2c (IC50 = 12.9 ± 0.7 μM) and 2h (IC50 = 15.1 ± 0.9 μM) exhibited promising activity relative to Donepezil. Kinetic analysis confirmed mixed- type inhibition by compound 2c, yielding a Km of 51.6 ± 1.5 μM, a Vmax of 0.61 ± 0.03 μmol/min/mg, and a Ki value of 6.8 ± 0.4 μM. Antioxidant evaluation indicated notable DPPH radical scavenging activity, with compound 2h showing 79.69% inhibition at 50 μg/mL.
DISCUSSION
The consistency between molecular docking, enzyme inhibition, and kinetic findings suggests that substituent-driven interactions play an important role in AChE inhibition. Additionally, the observed antioxidant activity highlights the therapeutic potential of these derivatives as multitarget agents capable of addressing both cholinergic dysfunction and oxidative stress associated with AD.
CONCLUSION
Collectively, the synthesized 2-mercaptobenzimidazole derivatives demonstrated promising acetylcholinesterase inhibitory and antioxidant properties. These findings support their potential as lead scaffolds for the development of novel multitarget therapeutic candidates for Alzheimer's disease.
Iqra Zulfqar, Syed Muzzammil Masaud, Asma Bukhari et al.· Current Medicinal Chemistry· 0 citations
Experimental findings identify compounds 8c and 9e as promising lead scaffolds for the development of next-generation inhibitors of urease and α-glucosidase.
Mohammad A. Alrofaidi· Journal of Visualized Experi...· 0 citations
This study reports a sustainable and environmentally friendly approach for the synthesis of novel pyrimidine Schiff base derivatives through a multicomponent grinding reaction conducted at room temperature under solvent-free conditions. The synthesis involved pyrimidine, various aldehydes, and p-toluenesulfonic acid as a catalyst. The obtained compounds (1–3) were evaluated for their potential anticancer activity against the breast cancer estrogen receptor alpha (ERα). Structural characterization was carried out using FT-IR, NMR spectroscopy, mass spectrometry, and elemental analysis. In addition, molecular docking studies were performed to investigate the binding interactions of the synthesized 1,4-dihydropyrimidine-5-carboxylate derivatives (1–3) with the ERα protein. Among the tested compounds, derivative (3) demonstrated the most promising biological activity, exhibiting an IC₅₀ value of 8.91 μg/L compared with cisplatin (cis-Pt) as the reference drug, along with the highest binding affinity toward ERα. These findings suggest that compound (3) may serve as a promising lead candidate for breast cancer therapy. Molecular modeling studies were conducted using the Molecular Operating Environment (MOE 2019) software, while toxicity prediction was performed using Osiris software.
Alaa M. Abu Alnjaa· Oriental Journal of Chemistr...· 0 citations
Cancer continues to be a leading cause of global mortality, highlighting the ongoing need for novel anticancer compounds that offer high efficacy with improved side effect profiles. In the present study, a series of 3H-1,2-dithiole-3-thione derivatives (DTT-S1-18) were synthesized as promising anticancer agents, and the structures of products were confirmed by spectral techniques. H2S-releasing experiments showed that most of the compounds released higher amounts of H2S slowly over time compared to standard ADT-OH. All compounds were tested for antiproliferative activity on HT-29, PC-3, MCF-7, and HUVEC cell lines. Compounds DTT-S6 (3-nitrophenyl derivative) and DTT-S8 (methionine derivative) have the lowest IC50 values of 41.6 and 38.9 µM on the MCF-7 cell line, respectively. Based on the wound healing and colony formation assays performed in MCF-7 cells, the wound areas were not significantly changed after treatment with compounds DTT-S6 and DTT-S8, whereas compound DTT-S8 at double IC50 dose inhibited colony formation by 81.82%. In addition, molecular docking, MD simulations, MM/GBSA binding free energy calculations, and binary QSAR analyses were performed to explore the potential target interactions and predicted activity profiles of the synthesized compounds toward inflammation-related proteins, including COX-1, COX-2, 5-LOX, and iNOS, thereby supporting the development of mechanistic hypotheses for future validation. Furthermore, structure-activity relationship (SAR) analyses were conducted to correlate the structural characteristics of the synthesized compounds with their H2S releasing potential and biological profiles. Overall, this work integrates experimental anticancer evaluation with computational pathway and structure-based cancer/inflammation analyses to characterize novel DTT-based H2S donors. The findings identify particularly compound DTT-S8, as a promising in vitro anticancer candidate, while the computational results suggest a putative involvement of inflammation-related targets, particularly the COX-2/5-LOX axis, which requires direct biochemical and cellular validation.
Semra Altunsoy, Y. Yilmaz, T. Güngör et al.· Molecular diversity· 0 citations
INTRODUCTION
Inflammation and oxidative stress play important roles in the development of various chronic diseases, necessitating compounds with dual therapeutic potential.
METHODS
A series of (E)-7-hydroxy-4-methyl-6-(3-(substituted phenyl)acryloyl)-2H-chromen-2-one (7a-m) were synthesized starting from 7-hydroxy-4-methyl coumarin. The synthesized compounds were evaluated for their in vitro antioxidant and anti-inflammatory activity Results: Compound 7a exhibited the most potent antioxidant activity with an IC50 value of 83.39 μM. Compound 7b was found to be nearly 1.5-fold more potent in inhibiting albumin protein denaturation than ibuprofen and diclofenac at 100 μg/ml. Compound 7b displayed the most potent inhibitory activity against TNF-α and weak inhibition against the COX-2 enzyme with an IC50 value of 4.32 and 419.04 μM, compared to standard ibuprofen (IC50 value of 5.0 μM against COX-2) and diclofenac (IC50 value of 21.0 μM against TNF-α). Molecular docking studies of compound 7b showed the highest docking score against TNF-α and COX-2 enzymes, compared to the standard celecoxib.
DISCUSSION
It was found that chloro at the 2nd position or methoxy at the 3rd position led to promising anti-inflammatory activity. Removal of the chloro group led to a decrease in COX-2 and TNF-α inhibitory activity. In the molecular docking studies, compound 7b shows a similar binding interaction against TNF-α and COX-2 as the standard celecoxib. The DFT studies showed favorable interactions, good stability, and moderate reactivity within the biological targets.
CONCLUSION
Based on the results of the present study, it is suggested that coumarin-chalcone derivatives may act as a lead for the synthesis of more potent antioxidants and anti-inflammatory compounds.
Dalaa Ali El-Jadayel, Husna Khalifa Al-Busaidi, Zainab Hamood Al-Balushi et al.· Anti-Inflammatory & Anti-All...· 0 citations
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