Neurodegenerative disorders and neuroblastoma represent major therapeutic challenges, and multitarget approaches have gained increasing attention. In this study, a series of thiosemicarbazone derivatives (5a-t) was evaluated for their inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase A (MAO-A), together with their cytotoxic effects and molecular interaction profiles. In vitro enzyme assays revealed nanomolar inhibition for several compounds. Notably, compound 5n exhibited potent and balanced multitarget activity with IC50 values of 104.28 nM (AChE), 23.04 nM (BChE), and 215.50 nM (MAO-A), surpassing galantamine (IC50 = 296.32 and 105.20 nM for AChE and BChE, respectively) and approaching the activity of clorgyline (IC50 = 401.68 nM). Kinetic studies confirmed strong enzyme binding, with Ki values of 92.42 nM (AChE) and 25.35 nM (BChE). Cytotoxicity assays against SH-SY5Y neuroblastoma cells showed selective antiproliferative effects, with compound 5n displaying an IC50 of 5.23 µM and a selectivity index of 8.6 relative to HUVEC cells. Molecular docking and MM-GBSA analyses revealed strong binding affinities (docking scores - 10.4 to - 15.4 kcal/mol; ΔG_bind - 55.9 to - 88.4 kcal/mol), which were further supported by molecular dynamics simulations. DFT calculations indicated favorable electronic properties (HOMO-LUMO gap: 0.098-0.116 eV), while ADME predictions suggested acceptable drug-like behavior and good oral absorption. These results identify thiosemicarbazone derivative 5n as a promising multitarget lead for the development of agents targeting cholinergic dysfunction, MAO-A inhibition, and neuroblastoma proliferation.

AIM:This study aimed to synthesize a new series of thiosemicarbazone derivatives (4a-r) as multifunctional antidiabetic candidates with dual α-glucosidase (α-Glu) inhibitory and antioxidant activities to address both hyperglycemia and oxidative stress in diabetes management. MATERIALS AND METHODS:Compounds were synthesized and characterized spectroscopically. The in vitro studies were done on compounds for α-Glu inhibitory and metal-chelating properties. The docking studies and MM-GBSA experimental analyses were implemented for the evaluation of binding strength, coupled with 500 ns molecular dynamics in order to validate the stability of the enzyme-ligand complex. ADME prediction tools were employed to evaluate pharmacokinetic suitability. RESULTS:Compound 4d (p-methylbenzyl) showing the strongest α-Glu inhibition (IC50 = 206.91 nM, Ki = 235.86 nM), significantly surpassing acarbose. Additionally, 4d demonstrated the most effective antioxidant activity (IC50 = 26.85 µg/mL). Computational findings confirmed its favorable binding free energy (-82.36 kcal/mol) and stable interactions with catalytic residues throughout the MD simulations. ADME predictions indicated good intestinal permeability and 89% oral absorption, suggesting improved pharmacokinetic behavior. CONCLUSION:Compound 4d emerges as a highly promising dual-function antidiabetic candidate with strong enzymatic inhibition, effective antioxidant action, and desirable drug-like features, making it a valuable lead for future optimization and further biological evaluation.

Diabetes mellitus (DM) is a metabolic condition commonly marked by increased blood glucose levels and effectively managed with α-glucosidase inhibitors. In this study, a novel series of 7-bromochromone-based thiosemicarbazones 4(a-r) was synthesized and assessed for their α-glucosidase inhibition. All the compounds demonstrated excellent inhibitory potential with IC50 values in the range of 97.87 ± 0.01 μM-353.34 ± 0.06 μM, vastly outperforming the standard inhibitor acarbose (IC50 = 871.40 ± 1.24 μM). Compound 4h, bearing a 2,3-dichlorophenyl substituent, showed the highest potency (97.87 ± 0.01 μM). Molecular docking and molecular dynamics (MD) simulations were conducted to investigate the binding interactions of these compounds within the α-glucosidase active site. Among the synthesized compounds, 4h demonstrated the most favorable docking configuration and stable binding interactions, suggesting its potential as a lead candidate in the development of novel antidiabetic agents.

The present study aimed to investigate the antidiabetic potential of a new series of thiosemicarbazone derivatives through integrated in vitro enzymatic assays and in silico molecular modeling. The synthesized compounds were evaluated for their inhibitory activities against α-glucosidase (α-Glu) and α-amylase (α-Amy) enzymes. Among the tested derivatives, compound 16 (2-chlorophenyl-substituted) demonstrated the most potent dual inhibition with IC50 values of 14.58 nM (α-Glu) and 88.37 nM (α-Amy), surpassing the reference drug acarbose in potency. Molecular docking analyses revealed that compound 16 formed stable interactions with Asn-214, Glu-276, Phe-157, and Tyr-71 in the α-Glu and Asp-197, Glu-233, and Lys-200 in α-Amy's active site. These key interactions were further supported by 250 ns molecular dynamics simulations, confirming the conformational stability of both complexes with average RMSD values below 2.0 Å and minimal ligand fluctuations. Energy decomposition analysis indicated that van der Waals and electrostatic interactions were the major contributors to the overall binding free energy. In silico ADME profiling predicted favorable pharmacokinetic properties, including high gastrointestinal absorption, good oral bioavailability, and compliance with Lipinski's rule of five, while no significant blood-brain barrier penetration was observed. The combined in vitro and in silico findings highlight compound 16 as a promising lead candidate for further optimization and development as a dual α-Glu and α-Amy inhibitor for the management of type 2 diabetes mellitus.

A new series of 6-hydroxychromone-based thiosemicarbazones 4(a-p) was synthesized and assessed for their antidiabetic (α-Glucosidase and α-Amylase inhibition) as well as antioxidant (2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2´-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)) activities. Among the synthesized compounds, compound 4k (IC50 = 1.18 ± 0.19 µg/mL) emerged as the promising α-Glucosidase inhibitor, significantly outperforming the reference drug Acarbose (IC50 = 7.33 ± 0.13 µg/mL). For α-Amylase inhibition, compound 4 g (IC50 = 13.61 ± 2.04 µg/mL) demonstrated excellent activity, compared to Acarbose (IC50 = 43.15 ± 5.22 µg/mL). In antioxidant assays, compound 4o (IC50 = 15.30 ± 1.70 µg/mL) exhibited the strongest DPPH radical scavenging effect, and compound 4 g (IC50 = 6.06 ± 0.15 µg/mL) showed the highest ABTS scavenging activity, surpassing the standard antioxidant Trolox (IC50 = 30.20 ± 5.14 & 18.19 ± 2.47 µg/mL, respectively). Remarkably, these derivatives showed greater efficacy compared to standard inhibitors, underscoring their promise as novel candidates for antidiabetic and antioxidant drug development. Molecular docking analysis demonstrated strong binding and critical interactions within the enzyme active sites. MD simulations confirmed the stability of 4k-α-Glucosidase and 4 g-α-Amylase, with RMSD values below 3.6 Å, low RMSF (< 2.8 Å) at the binding site, and sustained key interactions with Phe 158 and Tyr 151, respectively. The network pharmacology further supported the findings of molecular docking and simulation analysis.

A new series of hydrazones were prepared and assessed for their inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase-A (MAO-A) along with their antioxidant activity. Among the tested compounds, 5i displayed the maximum inhibitory activity with IC50 = 11.29 ± 0.98 nM for AChE, IC50 = 1.12 ± 0.41 nM for BChE, and IC50 = 102.70 ± 5.26 nM for MAO-A. Notably, compound 5i was found to be more potent than the standard. Additionally, the IC50 values obtained from antioxidant assays ranged from 9.22 ± 0.91 nM to 19.48 ± 0.05 nM, indicating the strong free-radical scavenging property. Structure-activity relationship (SAR) studies proved that electron-withdrawing substituents play a pivotal role in increasing the inhibitory efficiency and antioxidant capacity. To validate these results, molecular docking and dynamics studies were conducted to investigate the binding contacts and possible inhibition mechanisms in the active sites of the enzyme. DFT, GCR descriptors, and ESP analyses elucidated the electronic features governing the activity. The compounds exhibited moderate cytotoxicity in HUVEC cells, with IC50 values ranging from 35.94 to 64.27 µM, indicating a favorable safety profile within the tested concentration range. The outcomes highlighted the substantial multifunctional potential of the evaluated hydrazones as AChE, BChE, and MAO-A inhibitors with complementary antioxidant activity, and cytotoxicity results indicated their potential for further advancement in the management of neurodegenerative conditions.

Ectonucleotidases, including NTPDases and ecto-5'-nucleotidase (e-5'NT/CD73), regulate extracellular purinergic signaling by converting ATP to adenosine, a pathway critically involved in immune response, inflammation, and cancer progression. In this study, a novel library of 22 N-propylsulfonyl-substituted indole-based hydrazinecarbothioamides (5a-5v) was synthesized and structurally characterized. Biological evaluation against human e-5'NT and NTPDase1, -2, -3, and - 8 revealed that several compounds exhibited low micromolar inhibitory activity, with 5n (IC50 = 1.7 µM), 5o (IC50 = 1.7 µM), 5f (IC50 = 1.0 µM), and 5i (IC50 = 1.6 µM) emerging as the most promising derivatives, showing strong potency and isoform selectivity. Structure-activity relationship analysis indicated that both electronic and steric features of substituents significantly influence activity and enzyme preference. Molecular docking studies performed on e-5'NT demonstrated that active compounds adopt consistent binding modes within the catalytic pocket, stabilized by key residues such as Asp-506, Phe-500, Phe-417 and Arg-395. Binding free energy calculations (MM-GBSA) supported strong ligand-protein interactions ( ~ - 70 kcal/mol). The docking protocol was validated by redocking, yielding an RMSD value well below the accepted threshold. Molecular dynamics simulations (500 ns) confirmed stable complex formation, with low RMSD values (~ 1-3 Å), limited residue fluctuations, and persistent interactions with catalytic residues. Surface and compactness parameters (rGyr, SASA) remained stable, indicating consistent ligand accommodation. In silico ADME analysis suggested favorable drug-like properties for most compounds, particularly for the lead candidates. Overall, these findings identify 5n and 5o as the most promising lead compounds, supported by both experimental and computational results, and highlight this scaffold as a valuable platform for the development of selective ectonucleotidase inhibitors.

INTRODUCTION:SARS-CoV-2 has significantly impacted people's lives worldwide. The viral genome has undergone numerous unanticipated changes that have led to the creation of new varieties and raised concerns across the globe. As the bioactive phytochemicals from both natural and synthetic origins have become a promising therapeutic approach due to their high ability to suppress pathogenic viruses. METHODS:The current work reports 9 novel isatin hydrazide conjugates as inhibitors of the SARSCoV- 2 spike protein, using in vitro and in silico approaches. RESULTS:It's interesting to note that, except for compounds 3a, 3e, and 3h all the remaining compounds showed significant to high inhibition, with inhibitory values ranging from 91.50 to 77.40 %. Here, compounds 3b (86.80 %), 3c (89.30 %), 3d (81.60 %), 3f (87.30 %), 3g (84.40 %), 3i (91.50 %), and compound 3l (85.49 %) resulted in high inhibitory potential. While 3j compound with 77.40 % inhibition significantly inhibited the SARS-CoV-2 spike protein. With docking scores ranging from -7.1 to -9.1 kcal/mol, the molecular docking of these compounds showed an excellent fit of molecules in the spike protein receptor binding domain (RBD) with good interactions with the RBD's essential residues. Additionally, a 100 ns molecular dynamics simulation showed that the complexes 3i-6M0J and Narlaprevir-6M0J were highly stable. DISCUSSION:This study highlights the prospective therapeutic potential of new isatin hydrazide conjugates for the treatment of COVID-19 by identifying them as strong SARS-CoV-2 spike protein inhibitors that have been confirmed by docking and molecular dynamics. CONCLUSION:The results of these in vitro and in silico experiments suggest their medical potential in treating SARS-CoV-2 infection with high potency. Therefore, these tiny compounds have the potential to be therapeutic agents.

Cancer treatment struggles with toxicity, driving the development of targeted drug delivery systems like MOFs for better efficacy and reduced side effects in hepatocellular carcinoma HCC. This study was to evaluate the anticancer efficacy and biocompatibility of formulations, Zn-MOF, Zn-MOF/5FU, and FA-Cs/Zn-MOF/5FU against HepG2 cancer cells and LO2 normal cells at a 40 μM concentration. 5FU, a commonly used chemotherapeutic agent, demonstrated high cytotoxicity against HepG2 cells (70.39% inhibition, IC50: 22.4 ± 0.5 μM) but exhibited significant toxicity (22.86%) in normal cells, indicating its non-selective activity. Incorporating 5FU into Zn-based metal-organic frameworks (MOFs) (Zn-MOF/5FU) enhanced its efficacy (77.12% inhibition, IC50: 21.3 ± 0.2 μM), although it still caused 19.04% toxicity in normal cells. The functionalized nanoplatform FA-Cs/Zn-MOF/5FU exhibited the highest anticancer activity, 81.67% inhibition (IC50: 16.2 ± 0.6 μM), with least toxicity to normal cells, 11.02%, due to folate receptor targeting along with chitosan functionalization, which enhanced stability, drug loading, controlled release, and selectivity through increased cellular uptake. Zn-MOF without modification presented the lowest anticancer activity, 61.49% inhibition (IC50: 34.4 ± 0.6 μM), but it was biocompatible, having 16.76% toxicity. Thus, the structure-activity relationship supports the progressive enhancements of anticancer activity and selectivity in these functional modifications. These results confirm that FA-Cs/Zn-MOF/5FU presents the most promising anticancer effect among the series with controlled release, reduced toxicity, and improved cellular uptake. This study novel insights into targeted cancer therapy designs by using metal-organic frameworks (MOF) and functionalized drug delivery systems.

Alzheimer's disease (AD) is a neurological condition that predominantly affects the elderly population. Cholinesterase inhibitors (ChEIs) are effective medications for palliative and symptomatic relief in the management of AD. A series of new vanillin-based hydrazones 5(a-n) was synthesized and assessed for their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase A (MAO-A), along with their antioxidant properties. Compounds 5c and 5n were potent inhibitors of AChE and BChE, with IC50 = 0.88 & micro;M (Ki = 0.65 +/- 0.01 & micro;M) and 14.33 & micro;M (Ki = 12.30 +/- 0.50 & micro;M), respectively. In contrast, compound 5l showed significant MAO-A inhibition (IC50 = 0.16 & micro;M) and strong antioxidant metal chelating activity (IC50 = 26.98 & micro;g/ mL), surpassing the reference drug Clorgyline (IC50 = 1.98 & micro;M) and EDTA (IC50 = 59.26 & micro;g/mL), respectively. Molecular docking analysis revealed that compound 5c showed more favorable binding energies than the other synthesized derivatives across all three targets, forming key interactions within the catalytic active sites of AChE, BChE, and MAO-A. Molecular dynamics simulations (100 ns) confirmed that 5c remained stably bound within the active sites, maintaining consistent interactions with critical amino acid residues throughout the simulation period. The BChE-5c complex exhibited the highest structural stability (RMSD = 1.7 & Aring;), followed by AChE (2.23 & Aring;) and MAO-A (2.38 & Aring;), indicating minimal conformational deviation and stable protein-ligand interactions.

In this study, a series of 6-ethoxyphenyl-4-fluorobenzenesulphonate-based thiosemicarbazones (5a-w) were synthesized via a two-step process and structurally characterized by 1H NMR and 13C NMR spectroscopy. Their inhibitory activities against human carbonic anhydrase isoforms I and II (hCA I and hCA II) were evaluated, revealing potent inhibition at low nanomolar concentrations with IC50 values ranging from 56.36 to 230.17 nM for hCA I and 30.66 to 175.45 nM for hCA II. Compounds 5a, 5g, and 5n exhibited the highest enzyme inhibition, with 5a identified as the most potent in vitro inhibitor for both isoforms. Molecular docking studies and MM-GBSA binding free energy calculations demonstrated that compound 5n displayed the strongest binding affinity toward hCA I, stabilized by key interactions including π-π stacking, hydrogen bonds, and coordination to the catalytic zinc ion. Molecular dynamics simulations over 100 ns confirmed the stability and dynamic adaptability of the 5n-hCA I and 5g-hCA II complexes, preserving critical interactions essential for binding. Validation of the docking protocol yielded RMSD values below 2.0 Å, supporting the reliability of the computational approach. Overall, these findings highlight compounds 5n and 5g as promising lead molecules for selective inhibition of hCA I and hCA II, with potential applications in the treatment of carbonic anhydrase-related disorders.

In this study, twenty novel morpholino/pyrrolidino-sulfonyl-indole thiosemicarbazone derivatives (6a-j and 7a-j) were synthesized and tested for cholinesterase inhibition and anticancer activity. Compounds 6h and 7h stood out as the most potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC50 values as low as 0.15 μM and 0.12 μM, respectively, outperforming reference drugs tacrine and galantamine. Both also showed significant cytotoxicity against SH-SY5Y neuroblastoma cells, with IC50 values of 3.8 μM and 4.2 μM, and high selectivity indices (126 for 6h and 60 for 7h) compared to normal fibroblast cells, indicating therapeutic potential. Molecular docking and MM-GBSA analyses revealed strong binding affinities with docking scores between -8.7 and - 9.3 kcal/mol and ΔG bind ranging from -55 to -62 kcal/mol. Key residues such as Trp-86, Tyr-341, Tyr-337, and Tyr-124 in AChE and Trp-82, Phe-329, Trp-231, and Pro-329 in BChE facilitated stable hydrogen bonds and π-π stacking. Molecular dynamics simulations over 250 ns confirmed complex stability with low RMSD and RMSF values. These combined results highlight 6h and 7h as promising multitarget therapeutic candidates for neurodegenerative diseases and cancer.

A novel series of 4-thiomorpholinophenyl-thiosemicarbazones (3a-p) was synthesized and characterized by spectroscopic techniques. The compounds were evaluated for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), key enzymes associated with neurodegenerative disorders. All derivatives exhibited potent inhibition, with nanomolar IC50 values ranging from 11.36 to 34.17 nM (AChE) and 33.42 to 79.77 nM (BChE), comparable to standard drugs galantamine and tacrine. Compound 3l, bearing a benzyl group, showed the strongest dual inhibition (AChE IC50 = 11.36 nM) and compound 3n exhibited the highest BChE selectivity (Ki = 33.42 ± 2.38 nM). Anticancer activity was assessed against SH-SY5Y neuroblastoma and HEK-293 cell lines. Compound 3l demonstrated selective cytotoxicity against SH-SY5Y cells (IC50 = 21.11 ± 0.42 μM) with minimal toxicity toward HEK-293 cells (IC50 = 69.49 ± 4.27 μM, SI = 3.3), comparable to sorafenib. Molecular docking showed multiple π-π and hydrogen-bond interactions of 3l with AChE (Tyr-72, Tyr-337, Trp-286, His-447, Phe-295, Tyr-124) and 3n with BChE (Trp-231, Phe-329, Pro-285, Gln-119, Thr-120). MM-GBSA calculations indicated favorable binding energies (-70.74 and - 67.09 kcal/mol) driven by van der Waals and lipophilic forces. Molecular dynamics simulations confirmed stable complexes with RMSD ∼1.4 Å for ligands, ∼2.0 Å for proteins, persistent interactions, and reduced flexibility (RMSF ∼1.5 Å). ADME analysis suggested acceptable drug-like properties. These results highlight 3l and 3n as promising scaffolds for dual cholinesterase inhibition and selective anticancer activity.

Alzheimer's disease (AD) is known as one of the more devastating neurodegenerative diseases diagnosed in older people. Cholinesterase inhibitors (ChEI) can be used as an effective palliative treatment for AD. An extensive range of new biologically active 4-(diethylamino) salicylaldehyde-based thiosemicarbazone derivatives 5(a-u) was synthesized and evaluated as inhibitors of cholinesterase (ChE) and monoamine oxidase (MAO) enzymes. 2,3-Dichloro-substituted compound 5u was the most potent inhibitor of AChE and MAO-A with IC50 values of 12.89 and 96.25 nM, respectively. In contrast, the 2,3-dichlorophenyl-substituted compound 5a was the most powerful inhibitor of BChE, with an IC50 value of 124.72 nM. Structure-activity analysis revealed that the electron-withdrawing substituents on the phenyl ring play a crucial role in the inhibition potential of synthesized compounds. Compound 5a showed the strongest binding with 4BDS (-11.3 kcal/mol) via hydrogen bonds and π-interactions. Compound 5u exhibited high affinity with 1B41 (-8.2 kcal/mol), 2Z5X (-8.6 kcal/mol), and 2V5Z (-7.8 kcal/mol), forming key hydrogen bonds, salt bridges, and π-interactions, highlighting its multi-target potential. In silico ADME, pharmacokinetics, and drug-likeness studies were conducted and compared with the standard drugs galantamine and clorgyline.

A series of novel phenyl naphthalene-2-sulfonate-based thiosemicarbazones (5a-v) were synthesized and evaluated for their inhibitory activity against human carbonic anhydrases I and II (hCA I and hCA II). Compounds 5d and 5p demonstrated the highest inhibitory potency, with IC50 values of 4.32 ± 0.02 nM and 5.24 ± 0.03 nM for hCA I, and 3.89 ± 0.01 nM and 4.72 ± 0.01 nM for hCA II, respectively. Notably, compound 5d exhibited superior potency compared to the reference drug acetazolamide. The structure-activity relationship (SAR) analysis revealed that electron-withdrawing groups, particularly the dichlorophenyl group in 5d and 5p, enhanced inhibitory activity. Molecular docking and molecular dynamics simulations confirmed the high binding affinity of compound 5d, with docking scores of -9.7 kcal/mol for hCA I and -9.5 kcal/mol for hCA II. Stability in MD simulations further supported its potent inhibitory action. ADMET predictions suggested that compounds 5d and 5p have favorable pharmacokinetic profiles. In conclusion, phenyl naphthalene-2-sulfonate-based thiosemicarbazones, especially compound 5d, show strong potential as therapeutic agents targeting hCA I and hCA II.

Prolyl oligopeptidase (POP) is a compelling therapeutic target associated with aging and neurodegenerative disorders due to its pivotal role in neuropeptide processing. Despite initial promise demonstrated by early-stage POP inhibitors, their progress in clinical trials has been halted at Phase I or II. This impediment has prompted the pursuit of novel inhibitors. The current study seeks to contribute to the identification of efficacious POP inhibitors through the design, synthesis, and comprehensive evaluation (both in vitro and in silico) of thiazolyl thiourea derivatives (5a-r). In vitro experimentation exhibited that the compounds displayed significant higher potency as POP inhibitors. Compound 5e demonstrated an IC50 value of 16.47 ± 0.54 μM, representing a remarkable potency. A meticulous examination of the structure-activity relationship indicated that halogen and methoxy substituents were the most efficacious. In silico investigations delved into induced fit docking, pharmacokinetics, and molecular dynamics simulations to elucidate the intricate interactions, orientation, and conformational changes of these compounds within the active site of the enzyme. Moreover, our pharmacokinetic assessments confirmed that the majority of the synthesized compounds possess attributes conducive to potential drug development.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 μM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 μM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.

One of the highly expressed enzymes in the brain, prolyl specific oligopeptidase (POP), is a key target for the treatment of illnesses of the central nervous system including, autism spectrum, schizophrenia, Parkinson's, dementia, and Alzheimer's. In the current studies we report a series of indole based thiosemicarbazone as prolyl oligopeptidase (POP) inhibitors. Numerous approaches, such as Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and mass-spectrometry (MS) procedures, were used to confirm the structures of all substances. These compounds were evaluated against POP interestingly all these tested molecules significantly inhibit POP in vitro at very low doses (5.74-25.30 µM). Compound 3g displayed the highest inhibition with IC50 value 5.74 ± 0.27 µM. Kinetic studies of compounds, 3g, revealed concentration dependent type of inhibition with Ki value 4.31 ± 0.0012 µM. Furthermore, molecular docking was also performed to understand the binding modes of compounds, which correlates with our in vitro outcomes.

Diabetes mellitus has become a major global health burden because of several related consequences, including heart disease, retinopathy, cataracts, metabolic syndrome, collapsed renal function, and blindness. In the recent study, thirty Schiff base derivatives of 1,3-diphenylurea were synthesized and their anti-diabetic activity was evaluated by targeting alpha-glucosidase. The compounds exhibited an overwhelming inhibitory potential for alpha-glucosidase with higher potency ranging from 2.49-37.16 mu M. The most effective compound, 5h, showed competitive inhibition of alpha-glucosidase (K-i = 3.96 +/- 0.0048 mu M) in the kinetic analysis and strong binding interactions with key residues alpha-glucosidase in docking analysis, indicating its potential for better glycemic control in diabetes patients.