TL;DR
Hordenine emerges as a promising natural scaffold for developing carbonic anhydrase inhibitors with additional antioxidant properties, whereas alpinetin provides complementary radical scavenging activity.
Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that play essential roles in physiological processes and are recognized as important therapeutic targets for disorders such as glaucoma, epilepsy, and cancer. In this study, a series of azo-linked chalcone derivatives (1-10) was designed, synthesized, and evaluated for their inhibitory activity against human carbonic anhydrase isoforms I and II (hCA I and hCA II). All compounds demonstrated strong inhibitory activity in the low nanomolar range, with several derivatives surpassing the reference drug acetazolamide in potency. Remarkably, compound 1 exhibited the highest activity, particularly against hCA II, highlighting its potential as a lead candidate. Structure-activity relationship (SAR) analysis indicated that both the azo-linked aromatic moiety and the substitution pattern on the chalcone ring play critical roles in determining activity. Molecular docking studies revealed favorable binding interactions within the active site of the enzyme, which were further validated by molecular dynamics (MD) simulations conducted over 250 ns. In addition, in silico ADMET profiling suggested that the synthesized compounds possess acceptable pharmacokinetic properties, including good oral bioavailability, membrane permeability, and low predicted toxicity, supporting their drug-likeness. Hence, these findings demonstrate that azo-chalcone hybrids constitute a promising scaffold for the development of potent carbonic anhydrase inhibitors, with compound 1 identified as a strong candidate for further optimization and preclinical investigation.
AIMS Diabetes mellitus (DM) is a severe metabolic disease characterized by increased blood glucose levels due to reduced insulin action or secretion. This study aimed to synthesize new polyhydroquinoline (PHQ)-based acyl hydrazide derivatives and assess their potential as dual inhibitors of α-amylase and α-glucosidase enzymes. MATERIALS AND METHODS Various acyl hydrazide derivatives of PHQ were synthesized via a multi-step reaction and structurally deduced through modern spectroscopic techniques. These compounds were evaluated for their in vitro studies, while molecular docking was performed to gain mechanistic insights into their biological activities. RESULTS AND DISCUSSION In the series, compound (2c) emerged as the most potent inhibitor against both enzymes (IC50 = 0.44 ± 0.07 µM and 0.17 ± 0.01 µM, respectively), showing greater efficacy than acarbose. Density functional theory (DFT) analysis revealed valuable insights into the electronic properties and showed the best correlation with the biological targets. Moreover, molecular docking analysis showed good binding interactions with the active sites of both enzymes, which was supported by the experimental activities. CONCLUSION These integrated experimental and computational results demonstrate that the polyhydroquinoline scaffold represents a promising platform for developing next-generation antidiabetic therapeutics with enhanced efficacy and favorable safety profiles.
Polyphenol oxidase (PPO) is a vital polyphenol-metabolizing enzyme responsible for the enzymatic browning of fruits and vegetables. This study assessed the anti-PPO activity of protocatechualdehyde (PCA), yielding an IC50 value of 94 μM (95% CI: 91.8 to 96.4 μM). Kinetic analysis revealed that PCA acted as a reversible and competitive inhibitor of PPO. Molecular docking indicated that hydrogen bonding and hydrophobic interactions were the main driving forces for PCA-PPO binding. Fluorescence spectroscopy further demonstrated that PCA binding altered the microenvironments around tyrosine and tryptophan residues, leading to conformational rearrangements and partial unfolding of the enzyme, evidenced by significant fluorescence quenching. Molecular dynamics simulation demonstrated that PCA perturbed the secondary structure of PPO and caused stretching of its overall structure, thereby inhibiting the catalytic activity of the enzyme. Furthermore, PCA demonstrated excellent anti-browning activity by regulating phenolic metabolism, reducing membrane lipid peroxidation, enhancing the ascorbic acid-glutathione cycle, and modulating cell wall metabolism to delay cellular senescence. Collectively, these findings offer some valuable insights into the development of PPO inhibitor and anti-browning agent, and provide a theoretical foundation for the potential application of PCA in the area of food preservation.
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.
These findings highlight plumbagin as a potent multifunctional compound capable of mitigating MGO-induced glycation, and highlight plumbagin as a potent multifunctional compound capable of mitigating MGO-induced glycation.
To obtain molecules with dual activities of antioxidant effect and tyrosinase inhibition, a new series of Trolox derivatives (5a-5g) were constructed by incorporating thiosemicarbazone moieties into Trolox based on the molecular hybridization principle. In vitro antioxidant and tyrosinase inhibition assays showed that compound 5a exhibited better antioxidant activity than Vitamin C, and its tyrosinase inhibitory activity was 11 times that of kojic acid. Structure-activity relationship analysis revealed that Trolox and thiosemicarbazone moiety in 5a were crucial for its antioxidant and tyrosinase inhibitory activities. Kinetic assays identified 5a as a reversible mixed-type inhibitor. Furthermore, the mechanism underlying tyrosinase inhibition was elucidated using copper ion chelation, fluorescence quenching, CD spectroscopy, and molecular docking. The mechanism study indicated that 5a interacted with tyrosinase through copper chelation, hydrogen bonding, and hydrophobic interactions, thereby reducing the enzyme activity. Furthermore, 5a could prevent browning in fresh-cut potatoes through its antioxidant and anti-tyrosinase activities.