Aug 2026· Asian Journal of Chemistry· 0 citations· 21 references
TL;DR
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.
Abstract
Oxidative stress is a key driver of the pathogenesis of numerous chronic inflammatory and metabolic diseases emphasizing the requirement for the development of potent and selective antioxidant therapeutics. In present study, a series of novel piperazine-linked 1,3,5-triazine derivatives (6a-h) was rationally designed, synthesised and evaluated for antioxidant activity using integrated computational and experimental approaches. Molecular docking studies were carried out against myeloperoxidase (MPO; PDB ID: 1DNU), a heme-containing enzyme involved in reactive oxygen species (ROS) generation, to examine ligand–protein interactions and binding affinities. The synthesized compounds exhibited binding energies ranging from -3.816 to -4.987 kcal/mol. Among them, compound 6f, bearing a para-fluorophenyl substituent, shows the highest binding affinity (-4.987 kcal/mol). The enhanced binding was attributed to the formation of two hydrogen bonds with ARG27 and LEU97 and exceeded the binding energy of the reference antioxidant, ascorbic acid (-4.690 kcal/mol). The antioxidant potential was assessed by the DPPH free radical scavenging assay. Compound 6f displayed the strongest activity with an IC50 value of 14.15 ± 0.14 µM, which was comparable to that of ascorbic acid (IC50 = 14.06 ± 0.18 µM). Structure-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. The results identify piperazine-linked 1,3,5-triazine derivatives as promising antioxidant scaffolds and provide a strong basis for future myeloperoxidase inhibition studies and in vivo pharmacological evaluation.
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.
Chanda Ranjan, A. Mahesh, B. C. et al.· Current Computer - Aided Dru...· 0 citations
The present work describes the synthesis, molecular docking, and preliminary anticancer evaluation of a hybrid compound, product-
C
composed of a fluorinated sulfur heterocyclic core and an adamantane moiety. The synthesis method was designed to tune the electronic, lipophilic and structural properties of the compound through the introduction of CF₃, F and Cl functional groups, which are well known for the improving metabolic stability, physicochemical properties and drug-likeness. The structure of the synthesized compound was confirmed by
1
H and
13
C nuclear magnetic resonance (NMR) spectra. Molecular docking against phosphoinositide 3-kinase (PI3K), a protein target implicated in multiple cancers, showed that product-
C
exhibited a binding affinity of -10.6 kcal/mol, suggesting favorable interaction with the target. In parallel, the SRB (Sulforhodamine B) assay was used to evaluate the cytotoxicity of product-
C
toward PANC-1 cells. Preliminary results showed cell viabilities of 98.86% and 95.55% after exposure to 10 μM and 100 μM of product-
C
, respectively. These findings indicate that product-
C
displays low cytotoxicity toward PANC-1 cells under the tested conditions; however, they do not by themselves demonstrate marked antiproliferative activity.
M. Alamri, Yassine Riadi, A. Altharawi et al.· Arabian Journal of Chemistry· 0 citations
Twenty novel pyrrole-based hydrazide-hydrazone derivatives (GlyOH1-4, BAlaOH1-4, IleOH1-4, PheOH1-4, TrpOH1-4), bearing hydroxyl-substituted aromatic aldehydes and diverse amino acid scaffolds, were designed, synthesized in 83-95% yields, and fully characterized by FT-IR,
1
H-NMR and
13
C-NMR. All compounds exhibited radical-scavenging activity in DPPH and ABTS assays, with TrpOH-3 emerging as the lead (IC
50
3.96 ± 0.20 μM ABTS, 9.17 ± 0.09 μM DPPH), outperforming Trolox in both. SAR analysis revealed optimal activity from tryptophan scaffolds and catechol-like (2,3,4- or 2,4,5-trihydroxy) moieties, attributed to enhanced HAT/SET mechanisms and radical stabilization. Molecular docking of TrpOH-3 to Keap1 Kelch domain (PDB: 4L7B) yielded -6.25 kcal/mol, featuring H-bonds (Ser602, Ser363, Tyr525), water-mediated interactions, and Br-Tyr334 halogen bonding, supporting Nrf2 activation potential. ADME predictions indicated drug-likeness (1 Ro5 violation), though high MW limited CNS permeability. These multifunctional antioxidants hold promise for oxidative stress-related disorders.
E. Mateev, D. Tzankova, Valentin Karatchobanov et al.· Pharmacia· 0 citations
Background/Objectives: The thiazole ring is one of the core structures frequently favored in the design of new active compounds. Methods: A series of thiazole derivatives bearing a benzodioxole scaffold (1-9) were synthesized and evaluated for their antioxidant, anticholinesterase, and antidiabetic activities. Results: Antioxidant assays (ABTS and DPPH) revealed that compounds bearing 4-trifluoromethyl (compound 8) and phenyl (compound 9) moieties exhibited the strongest radical scavenging activities, attributed to efficient hydrogen atom transfer and extended π-conjugation, respectively. Enzyme inhibition studies showed that electron-withdrawing substituents such as 4-SO2CH3 (compound 3) and 3,4-diCl (compound 5) enhanced both AChE/BChE and α-amylase/α-glucosidase inhibition, surpassing the activity of acarbose in antidiabetic assays, while electron-donating groups reduced potency. Molecular docking and MD studies have shed light on the interactions of the active compounds. In addition, in silico ADMET predictions for the compounds have been performed. Conclusions: These results indicate that the thiazole-benzodioxole scaffold is a promising framework for developing multifunctional agents with combined neuroprotective, antidiabetic, and antioxidant activities.
Tuğçe Çaklılı, Yusuf Sıcak, Somdatta Y. Chaudhari et al.· Pharmaceuticals· 0 citations
The rise of microbes resistant to nearly all classes of antimicrobial drugs has become a severe public health problem in recent years. In this study, a new series of Schiff-base triazole hybrid derivatives was designed and synthesized and their in silico and biological evaluations were conducted to explore their antimicrobial potential. To gain deeper mechanistic insight, the synthesized compounds were subjected to a comprehensive computational workflow that included molecular docking, ADME profiling, DFT calculations, and MD simulations. Molecular docking studies revealed promising binding affinities ranging from -7.00 to -10.8 kcal/mol, placing these compounds on par with clinically established reference drugs in terms of target engagement. Among the series, compound 6j emerged as electronically favourable, exhibiting the lowest HOMO-LUMO energy gap (-0.15163 Hartree) as determined by DFT analysis, a characteristic often associated with enhanced chemical reactivity and biological interaction potential. The dynamic behaviour of the most promising protein-ligand complexes was further interrogated through 100 ns MD simulations, which confirmed robust structural stability throughout the simulation trajectory. Complementing these findings, ADME profiling established that the compounds fulfil the criteria outlined by Lipinski's Rule of Five, underscoring their suitability as orally bioavailable drug candidates. On the biological front, in vitro antimicrobial evaluation against a panel of clinically relevant bacterial and fungal strains yielded encouraging results. Compound 6j demonstrated meaningful antifungal activity, with MIC values spanning 500-1000 μg/mL, while compound 6d stood out for its potent antibacterial performance, achieving an MIC of 500 μg/mL. Collectively, these findings position Schiff-base triazole hybrids as structurally versatile and biologically promising scaffolds, warranting accelerated pharmacological exploration toward the development of next-generation antimicrobial therapeutics.
Javed Khan, Anjali Rani, Mohd Aslam et al.· Bioorganic chemistry (Print)· 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
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