α-Glucosidase inhibition is an important approach for controlling postprandial hyperglycemia in diabetes mellitus. In this study, a series of furan-linked 1,3,4-thiadiazole derivatives, including bis-Schiff bases 4a–c, bis-amide derivatives 5a–c, and macrocyclic cyclamide 8 were synthesized using a microwave/ultrasound-assisted protocol. The method provided a practical route to the target compounds with reduced reaction time; however, its environmental advantages are discussed cautiously because chlorinating and dehydrating reagents such as POCl3 and PCl5 were used. The structures of the synthesized compounds were characterized by FT-IR, 1H NMR, 1³C NMR, EI-MS, and elemental analysis. For compound 8, DFT/GIAO-NMR calculations were applied as supportive evidence to compare possible isomeric/tautomeric forms, and the revised correlation analysis suggested isomer C as the most probable structure. The synthesized compounds were evaluated for in vitro α-glucosidase inhibition, where compound 8 showed the highest activity in the tested series, with an IC50 value of 0.56 ± 0.031 µg/mL, comparable to acarbose (0.597 ± 0.022 µg/mL). Molecular docking suggested a favorable predicted binding mode for compound 8 within the selected α-glucosidase-related protein models, while 100 ns molecular dynamics simulations and MM/PBSA analysis supported the predicted stability of the compound 8–protein complex through stable RMSD, RMSF, Rg, SASA, hydrogen-bonding behavior, and binding free-energy trends. These computational results are presented as complementary support for the experimental findings and should not be considered independent confirmation of biological activity. Overall, compound 8 was identified as the most active α-glucosidase inhibitor among the synthesized derivatives, but further structural confirmation, expanded analogue synthesis, selectivity testing, cytotoxicity evaluation, and in vivo studies are required before drawing pharmacological or drug-development conclusions.
Numerous human diseases involving diabetes, Alzheimer’s disease, and inflammation have risks to human health and relation linking them via various causative factors and entanglements. Molecular hybridization was revealed as an enormous tool recently applied for the design of multitargeted drugs providing potent hybrid products. The study aimed for the synthesis of novel pyrazole–naphthalene–heterocycle hybrid and related functionalized analogues as possible multi-targeted bioactive agents. New pyrazole–naphthalene–thiazole and the corresponding pyrimidine analogue hybrids and those possessing aminophenylenone moiety were synthesized through efficient molecular hybridization strategies. The in vitro antioxidant, anti-diabetic, anti-Alzheimer, anti-arthritic, and anti-inflammatory activities was performed. Molecular docking was simulated to rationalize the observed bioactivities. Density Function Theory (DFT) study was performed to understand the electronic properties and reactivity. Drug likeness and pharmacokinetic analysis (via ADME) were also conducted. Synthesis of the targeted structures and structural elucidation was successfully achieved. Compound 5a exhibited the most potent and broad-spectrum profile, showing high free-radical scavenging capacity (TAC: 80.08 mg GAE/g), multi-enzyme inhibitory effects against α-amylase, α-glucosidase, and aldose reductase, and strong COX-1, COX-2, and 5-LOX inhibition. Interestingly, compound 4b demonstrated superior acetylcholinesterase inhibition (78.26%, IC50 = 6.71 µg/mL), indicating selective anti-Alzheimer potential. SAR analysis highlighted the role of π-conjugated aromatic systems, electron-donating substituents, and balanced lipophilicity in multi-target activity. Molecular docking rationalized the afforded bioactivities, revealing strong binding affinities and interactions within the active sites of the target supporting the experimental results. DFT explained comprehensively the electronic properties and reactivity of the enone product 5a in addition to comprehending such molecule’s stability. Drug likeness and pharmacokinetic analysis of compounds 4b and 5a predicted the physicochemical characteristics and affinities. The study findings suggest that structurally modified pyrazole-naphthalene-arylamino hybrid 5a incorporating enone linker, in particular, is a promising lead scaffold for further optimization toward multi-target therapeutic agents.
A series of heterocyclic derivatives incorporating the pyrano[3,2-c]quinoline-2,5-dione framework were successfully synthesized via nucleophilic substitution reactions of 6-ethyl-4-chloropyrano[3,2-c]quinoline-3-carbaldehyde 2 with several sulfur nucleophiles. Furthermore, aldehyde 2 underwent condensation reactions with various nucleophilic reagents, such as primary amines, and selected cyclic and acyclic active methylene compounds. The optimized geometrical structure of the starting aldehyde 2 was obtained through density functional theory (DFT) calculations performed at the B3LYP/6–311++G(d,p) level of theory. These computations were employed to evaluate several molecular parameters, including the molecular electrostatic potential (MEP), Fukui functions, frontier molecular orbital (FMO) characteristics, and nuclear magnetic resonance (NMR) properties. The DPPH radical scavenging activity of all synthesized derivatives was evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The results revealed that compounds 4, 7, and 9 exhibited the highest radical scavenging activity among the synthesized derivatives, although their activity remained lower than that of ascorbic acid. PL emission spectra and CIE 1931 chromaticity coordinates confirmed tunable fluorescence across the synthesized compounds, governed by molecular structure and physical state. Compounds 5 (yellow–green) and 6 (gold–yellow) proved highly effective for latent fingerprint visualization, yielding sharp ridge details on porous, nonporous, and multicolored substrates. Additionally, compounds 11 (violet), 8 (blue), and 3 (green–yellow) were formulated into stable, humidity-resistant luminescent inks, highlighting strong potential for anticounterfeiting and secure data encoding.
A major challenge in sustainable organic synthesis is the design of durable, reusable, and effective heterogeneous catalysts. Magnetic porous catalysts are a promising solution that not only possess catalytic activity but also can be readily recovered. In this work, a multifunctional Fe3O4@COF-SO3H catalyst was designed and synthesized using the combination of magnetic Fe3O4 nanoparticles, porous COF structure, and acidic sulfonic groups. This catalyst can provide the simultaneous improvements of accessibility, recyclability, and catalytic efficiency. FT-IR, XRD, SEM, TEM, BET, TGA, EDX, and VSM techniques have been used to thoroughly characterize the catalyst. Fe3O4@COF-SO3H was demonstrated to be an efficient catalyst for the multicomponent synthesis of pyrano and pyrido[2,3-d]pyrimidine derivatives under mild reaction conditions. The protocol offers a large selection of products with favorable yields (90–98%), and a convenient reaction time (7–25 min) using only 6 mg of catalyst. The catalyst is also very recyclable, and little loss of activity after 8 consecutive recycling. Fe3O4@COF-SO3H is a suitable platform for the sustainable synthesis of biologically relevant heterocycles, due to the magnetic separation, accessible acidic sites, and porous framework.
The increasing prevalence of drug-resistant Candida albicans, particularly in biofilm-associated infections, highlights the urgent need for structurally novel antifungal agents. The objective of this study was to design, synthesize, and evaluate 7-azaindole–incorporated 1,3,4-oxadiazole hybrids 5(a–n) as potential antifungal and antibiofilm agents. The novelty of this work lies in integrating 7-azaindole and 1,3,4-oxadiazole pharmacophores into a single hybrid framework and evaluating their biological, structural, and computational properties. The target compounds were synthesized via a three-step protocol in yields of 80–94% and characterized using LC–MS, FT-IR,1H NMR, and 1³C NMR spectroscopy, while SCXRD analysis was performed for lead compound 5j. Antifungal evaluation against C. albicans revealed MIC values of 8–64 µg/mL. Compound 5j exhibited activity comparable to fluconazole, with MIC and MFC values of 8 and 32 µg/mL, respectively. It inhibited biofilm formation by 71.56 ± 1.28% and filamentation by 64.18 ± 1.21%. qRT–PCR analysis showed downregulation of HWP1 and ALS3 to 0.35 ± 0.02- and 0.39 ± 0.02-fold, respectively. Molecular docking suggested favorable predicted interactions of 5j with ALS3, with a Glide score of −7.89, while DFT calculations showed a HOMO–LUMO energy gap of ΔEg = 4.875 eV. Overall, compound 5j represents a promising lead against C. albicans biofilm-associated infections.
Epidermal growth factor receptor (EGFR) overexpression plays a critical role in breast cancer progression, metastasis, and resistance to chemotherapy, making EGFR an important therapeutic target for the development of novel anticancer agents. This study aims to design, synthesize, and biologically evaluate a new series of indazole- and theophylline-substituted 1,3,4-thiadiazole derivatives as the potential EGFR inhibitors against human breast cancer cells. A library of novel thiadiazole derivatives was synthesized through multistep synthetic protocols and structurally characterized using standard spectroscopic techniques. The anticancer activity of the synthesized compounds was evaluated against MCF-7 human breast cancer cells using cytotoxicity assays. Molecular docking studies were performed to investigate the binding interactions of the compounds within the EGFR active site. Furthermore, the most active compound was subjected to mechanistic studies including EGFR phosphorylation inhibition, apoptosis induction, AKT signaling analysis, and cell cycle distribution assays. Among the synthesized derivatives, the compound 4n demonstrated the most potent cytotoxic activity against MCF-7 cells with an IC50 value of 22.92 & micro;M. Molecular docking analysis revealed a strong binding affinity toward EGFR (-8.29 kcal/mol), which was superior to that of the reference ligand. Biological investigations confirmed that compound 4n effectively inhibited EGFR phosphorylation and suppressed downstream AKT signaling. In addition, the compound significantly induced apoptosis (15.32%) and caused cell cycle arrest at the sub-G2/M phase, indicating its ability to inhibit breast cancer cell proliferation through EGFR-mediated pathways. The findings demonstrate that indazole- and theophylline-substituted 1,3,4-thiadiazole derivatives, particularly compound 4n, possess promising EGFR inhibitory and anticancer activities. The combined synthetic, computational, and biological results suggest that compound 4n may serve as a potential lead candidate for the development of targeted therapeutics against EGFR-positive breast cancer.
Neuroinflammation and oxidative stress are primary drivers of neurodegenerative diseases. Consequently, the development of multi-target-directed ligands has emerged as a promising therapeutic strategy. In this study, a novel series of hydroxypyranone-dithiocarbamate hybrids was designed, synthesized, and evaluated for its neuroprotective potential. Safety and intracellular ROS mitigation were assessed via MTT and DCFDA assays in LPS-induced SH-SY5Y neuroblastoma cells, while selective toxicity was profiled against MDA-MB-231 breast cancer and healthy HEK293-T cells. Comprehensive in silico profiling included ADMET predictions, molecular docking, and 100-ns molecular dynamics simulations targeting the anti-inflammatory cytokine IL-38. The in vitro results indicated that Compound 2, featuring a thiazolidine ring, emerged as the most promising lead derivative. It established a safe therapeutic window at 10 & micro;M in neuronal cells while exhibiting specific cytotoxicity against cancer lines. Cytotoxicity evaluations on healthy HEK293-T cells revealed that the compounds possess a high safety profile, with IC50 values exceeding 100 & micro;M. Compound 2 significantly reduced oxidative stress (mitigating LPS-induced ROS accumulation to 83.54% at a 10 & micro;M dose), while in silico models, supported by highly stable thermodynamics (Delta G similar to-19 kcal/mol), indicated that the IL-38 interface might serve as a plausible target for this novel scaffold. In conclusion, the integration of synthetic chemistry, in vitro biological evaluations, and computational thermodynamics reveals that hybridizing hydroxypyranone and dithiocarbamate pharmacophores offers a highly effective and safe scaffold for discovering novel neuroprotective agents targeting neuroinflammation.
High-energy-density materials often suffer from a tradeoff between detonation performance and sensitivity, making the design of stable yet powerful compounds challenging. In this work, three novel energetic compounds derived from 4H,8H difurazano[3,4-b;3 ',4 '-e] pyrazine (DFP) were computationally designed to address this issue. The results reveal that the designed DFP derivatives have high densities (>1.80 g/cm(3)), high enthalpy of formation (>685 kJ/mol), and good detonation performance (D > 7.68 km/s, p > 23.87 GPa), and they were compared with previously synthesized DFP compounds. The homolytic bond dissociation energies for C-NO2 bonds (>210 kJ/mol) and impact sensitivity (h(50) > 29 cm) suggest satisfactory stability and moderate sensitivity of the designed DFP derivatives. Analysis of aromaticity indices and planarity parameters suggest that DFP derivatives are stabilized by pi-electron delocalization within rings, bond length equalization, and a flat molecular structure. These results validate that this work on DFP-fused tricyclic backbone provides a viable approach toward designing, screening, and identifying promising high-performance energetic compounds.
While dual cholinesterase (AChE/BChE) inhibitors are urgently needed for Alzheimer's disease (AD) management, finding effective multi-target agents remains challenging. To address this, we designed and synthesized a novel series of thiazole-bearing compounds and evaluated their dual anticholinesterase and antioxidant potentials. The antioxidant capacities were tested via CUPRAC, FRAP, and DPPH assays, revealing compounds 1 and 8 as the most active derivatives with DPPH IC50 values of 62.510 +/- 0.027 mu M and 65.190 +/- 0.025 mu M, respectively]. For ChE inhibition, compound 3 emerged as a highly potent dual competitive inhibitor, outperforming the standard drug donepezil, with IC50 values of 1.440 mu M for AChE and 3.620 mu M for BChE. In silico studies elucidated the molecular basis of this activity; induced-fit docking revealed strong binding affinities for compound 3 with Glide scores of -9.82 kcal/mol (AChE) and -10.76 kcal/mol (BChE). Subsequent 500 ns molecular dynamics (MD) simulations confirmed the stability of these complexes, exhibiting low average protein RMSD values (2.25 & Aring; for AChE; 2.19 & Aring; for BChE) and highly favorable average MM/GBSA binding free energies (Delta Gbind) of -68.81 kcal/mol and -61.82 kcal/mol, respectively. Additionally, DFT calculations (MEP and FMO) were performed to elucidate the electronic properties correlating with the bioactivity. This study presents a novel thiazole scaffold as a promising lead for developing effective multi-target agents against AD.
Developing novel and simple methods for alpha, beta unsaturated gamma-lactams is of prime importance for discovering new antibiotics through late stage modification of lactams. Herein, we report an easily adaptable procedure for the preparation of alpha, beta unsaturated gamma-lactams from easily available and economical starting materials. Most of the literature methods employed transition metal to construct gamma-lactam ring, whereas the present method operates under metal free condition. The reaction involves sequential alkylation and acylation of amine, in-situ generation of phosphorus ylide, followed by intramolecular Wittig reaction.
A novel magnetic Zr(IV) catalyst derived from natural bioorganic humic acid (Fe3O4@HA-ZrOCl2) was prepared and characterized using TEM, FESEM, EDX, XRD, VSM, and FT-IR. The effectiveness of the Fe3O4@HA-ZrOCl2 nanocomposite as a catalyst was tested in a three-component condensation reaction of thiourea/urea, aldehyde, and ethyl acetoacetate to produce 3,4-dihydropyrimidinones. This catalyst successfully promoted the three-component Biginelli reaction without solvents at 70 degrees C, yielding dihydropyrimidinones in good to excellent yields. After adding warm EtOH to the reaction mixture, Fe3O4@HA-ZrOCl2 could be easily separated using an external magnet. The Zr(IV) magnetic nanocomposite demonstrated superior recyclability, allowing it to be reused multiple times with minimal loss of activity. Utilizing an external magnetic field simplifies the recovery of the catalyst, conserving time and energy by eliminating the need for filtration or decantation. Our procedure offers several advantages, including high quantitative yields, straightforward product isolation, easy catalyst separation and recovery, and reduced reaction times. [GRAPHICS]
Efficient and recyclable catalytic systems for carbon-nitrogen (C-N) bond formation remain a key challenge in green organic synthesis. Here, a novel magnetic Fe3O4@ZIF-8-Cu nanocatalyst was synthesized and fully characterized. Detailed structural studies established that a core-shell composite with a high surface area, large porosity, uniform copper dispersion, and good magnetic properties, which enables quick recovery, was successfully prepared. The catalyst exhibited high efficiency in the synthesis of diaryl guanidines with yields up to 95% under mild conditions. Notably, the catalyst retains its structure and catalytic performance in repeated reactions. Overall, this article presents an efficient, magnetically separable, and greener catalytic platform for the production of diaryl guanidines, which serve as useful scaffolds in organic pharmaceutical and synthetic chemistry. The complementary properties of the magnetic core, porous shell, and available copper active sites make Fe3O4@ZIF-8-Cu a promising alternative to conventional homogeneous copper catalysts.
Balancing high energy density with high insensitivity (high H50) remains a challenge for energetic materials (EMs). While machine learning (ML) has accelerated molecular discovery, current research has largely overlooked the 8-nitro-2,6-dihydrotetrazolo[1,5-c]pyrimidin-5(3H)-one scaffold in systematic high-throughput screening, despite its nitrogen-rich and structurally rigid nature. This work presents an integrated ML-aided high-throughput framework to explore this promising yet underexplored core. A virtual library of 14,300 derivatives was constructed using 23 energetic substituents. Based on density functional theory (DFT)-calculated data for 554 representative samples, predictive models were developed for ten critical physicochemical properties. The Extreme Gradient Boosting (XGBoost) algorithm demonstrated superior performance, enabling the efficient identification of 20 elite candidates from the massive library. DFT validation confirmed high predictive fidelity with relative errors mostly below 2%. This research not only unlocks the potential of the tetrazolo-pyrimidinone scaffold but also provides a scalable, data-driven paradigm for the rational design of high-performance functional materials.
Schiff base metal complexes continue to attract considerable attention due to their tunable coordination geometries and promising biological applications. In this study, Co(II), Ni(II), Cu(II), Zn(II), and Pd(II) complexes of 1-(((4H-1,2,4-triazol-yl)imino)methyl)naphthalen-2-ol (HNAT) were designed and well characterized using spectroscopy, analytical, and computational methods. Based on analytic and spectroscopic techniques, the geometry of the complexes is confirmed, which indicates octahedral for Co(II), square planar for Ni(II), Cu(II), Pd(II), and tetrahedral for Zn(II) complexes. The proposed geometries were further supported by DFT calculations. The powder X-ray diffraction patterns show that the ligand and its complexes are crystalline. The crystallite sizes of the ligand and its metal complexes [Co(II), Ni(II), Cu(II), Zn(II), and Pd(II)] were determined as about 44, 24, 48, 23, 35, and 31 nm, respectively, which are considered nanocrystalline. The PXRD pattern of the ligand is quite different compared to the metal complexes, indicating the existence of new crystalline phases with the formation of new complexes. DNA-binding studies ensured that Cu(II) complex has significantly high Kb value, suggesting its strong ability to interact with DNA, which enhances effective pi-pi stacking with DNA base pairs. In addition, the antimicrobial activity of the Ni(II) complex displayed broad spectrum activity with MIC of 3.65, 4.51, 4.44, and 4.86 & micro;g/mL against K. pneumoniae and E. coli, S. aureus, and S. epidermidis. In addition, cytotoxicity of Cu(II) and Zn(II) complexes showed high activity against HepG-2, MCF-7, and HeLa cell lines. The EGFR (PDB: 4HJO) molecular docking indicated the greatest binding affinity with the Cu(II) complex (-10.32 kcal mol-1), which was consistent with the experimental findings. These results demonstrate the potential of metal complexes in the treatment process and also give structure-activity information to use in designing new drugs.
The present study introduces a sustainable and green approach for the synthesis of pyrimido [4,5-d]pyrimidine derivatives, using Rumex vesicarius extract as a green catalyst in a multicomponent reaction. This methodology exploits the catalytic potential of phytochemicals to promote the one-pot condensation of substituted aldehydes, barbituric acid, and urea under mild conditions. By replacing conventional synthetic methods with a renewable biocatalyst, the process eliminates the need for expensive catalysts and harsh reaction conditions, offering key advantages such as excellent yields, shorter reaction times, operational simplicity, and the use of eco-friendly catalyst. This approach highlights the potential of plant-based catalysts in the synthesis of heterocyclic compounds.
To achieve the rising demand of photovoltaic materials, a series of small non-fullerene chromophores (TMS1-TMS7) with A-pi-D-pi-A architecture were designed via structural modulation of reference compound (TMSR) by incorporating terminal acceptors. Density functional theory (DFT) and time-dependent DFT (TD-DFT) analyses were computed at M06/6-311G (d,p) level to explore opto-electronic characteristics of the aforementioned derivatives. Frontier molecular orbitals (FMOs), density of states (DOS), absorption maxima (lambda(max)), transition density matrix (TDMs), open-circuit voltage (V-oc), and electron hole analyses were performed to comprehend photovoltaic response. Energy gap reduction was found in the range of Delta E = 2.631 to 1.813 eV with enhanced absorption ranging from 584.03 to 832.16 nm in solvent chloroform. Similarly, global reactivity parameters (GRPs) were conducted utilizing HOMO and LUMO energies. Moreover, V-oc was performed in conjunction with polymeric donor PCBM and all tailored compounds show reasonable results with respect to reference compound. Interestingly, among all chromophores, TMS7 was noted with the lowest energy gap (1.813 eV), maximum lambda(max) (832.165 nm) and remarkable efficiency, demonstrating promising photovoltaic response. This work revealed that designed compounds may appropriate for promising organic photovoltaics (OPVs) material. [GRAPHICS]
Chalcone-based semiconductors are promising for optoelectronic devices but are limited by instability and poor charge transport. This study overcomes these limitations by incorporating newly synthesized phenanthrenyl chalcone (PH) derivatives into PFO and PEO polymer hosts. PH-PFO films exhibited amorphous morphology, reduced energy gaps (2.96-2.98 eV), and efficient blue emission, indicating enhanced electronic interaction. In contrast, PH-PEO films retained crystalline aggregates and higher energy gaps. Electrical measurements showed significantly lower turn-on voltages for PH-PFO diodes (9.27-10.37 V) compared to PH-PEO (11.63-13.94 V), confirming improved charge injection. These results demonstrate the novelty of PH-PFO composites as the efficient active layers for organic semiconductive diode applications.
The search for novel potent anticancer agents is considered a rapidly advancing field and viewed as a constantly evolving area within medicinal chemistry. Twelve new compounds with quinoline side chains connected to bis-oxadiazoles and terminal lipophilic aryl portions with substantial substituent functions were created and synthesized using the EDC coupling reaction in an effort to find new treatments for the cancer epidemic. These compounds were structurally deduced using modern spectroscopic techniques (1H-,13C-NMR, and HRMS). Based on the EGFRWT inhibitory effects, compounds 7c and 7 l exhibited the most potent inhibitory activity with IC50 values of1.75 +/- 1.10 mu M and 1.60 +/- 0.25 mu M, when compared to Erlotinib (IC50 = 2.04 +/- 0.78 mu M). Additionally, it demonstrated notable activity against HT-29 cells, with an IC50 value of 6.65 +/- 0.47 mu M. In contrast, compound 7 l showed the highest selectivity for MCF-7 inhibition (IC50 = 5.67 +/- 2.70 mu M), outperforming the reference drug doxorubicin, which displayed an IC50 value of 6.44 +/- 1.39 mu M. Compound 7f inhibited cell viability by 97.42%, indicating it is the least cytotoxic compared to 7a and 7 l on the normal NCM460 cell line. The binding interactions of the best inhibitory ligands within the active region of breast cancer in EGFR were further verified by molecular docking predictions, which highlighted the significant hydrophobic and hydrogen-bonding interactions (PDB code: 1M17). The drug-like characteristics of these chemical structures (7a-7l) were confirmed by pharmacokinetic investigation of the newly synthesized oxadiazoles, which revealed positive qualities with regard to absorption, distribution, metabolism, excretion, and toxicity (ADME-T). As a result, it is strongly advised that these agents be studied further in clinical trials.
