Future medicinal chemistry最新文献

Aims: This study aimed to evaluate the behavioral and biochemical effects of synthesized flavonols (1-10) as potential nootropic, antidepressant, and antistress agents.

Materials and methods: Behavioral assessments were conducted using animal models to evaluate memory impairment, depression, and stress responses. The cognitive effects of flavonols were analyzed using spontaneous alternation, discrimination ratio, and step-down latency tests, while antidepressant activity was determined through forced swim (FST) and tail suspension (TST) tests.

Results: All synthesized flavonols (1-10) significantly improved spontaneous alternation and discrimination ratios and increased step-down latency compared to the amnesic group. These compounds also markedly reduced immobility time in both FST and TST, indicating strong antidepressant-like effects. Biochemical analyses supported these behavioral outcomes by revealing enhanced cholinergic activity and reduced oxidative stress. Molecular docking studies against acetylcholinesterase (PDB IDs: 4EY7 & 6O4W) showed strong binding affinities, particularly for flavonol derivatives, through key hydrogen-bonding and π-π interactions.

Conclusions: Flavonols (1-10) demonstrated significant behavioral, biochemical, and computational evidence of neuroprotection, suggesting their therapeutic potential in managing cognitive dysfunction, depression, and stress-related disorders.

Aim: A series of novel 1, 4-naphthoquinone-benzene sulfonamide hybrids were designed and synthesized in order to explore the anticancer activity of 1, 4-naphthoquinone and benzene sulfonamide derivatives.

Materials & methods: 1,4-naphthoquinone-benzene sulfonamide hybrids were synthesized and characterized using ¹HNMR and ¹³CNMR followed by traditional chemical synthesis methods techniques. Then, synthetic compounds were evaluated in vitro for their potentials to anticancer activity.

Results: Derivative 4m displayed the most potent antiproliferative activities against bladder cancers (T24 cells) with the IC₅₀ value of 8.12 μM. Further pharmacological experiments have shown that 4m can inhibit the formation of T24 cells colonies and induce cell apoptosis by downregulating the expression of Bcl-2, caspase-3, caspase-8, caspase-9, and Fas protein, and upregulating the expression of P21 and Cytochrome c protein. It also has an inhibitory effect on the migration of cancer cells. Moreover, 4m showed potent anti-tumor activity in vivo.

Conclusion: Present study highlighted compound 4m could be a potential anti-bladder cancer agent in future.

Aim: To synthesize a series of new 5-oximidazoline-sulfadiazine hybrids 7a-l and assess their anti-cancer (in vitro and in vivo) activities.

Materials and methods: The antiproliferative activity was assessed against the hepatocellular carcinoma (HepG2) cell line. Moreover, the in-vitro enzymatic inhibitory activity against EGFR-TK for all the synthesized members was then assessed. In addition, cell cycle analysis, apoptosis induction, and in-vivo toxicity assessment of the most active analog were also conducted.

Results: The analog 7l with 3,4,5-trimethoxybenzylidene in the 5-oximidazoline ring revealed good cytotoxicity and selectivity against the HepG2 cancer cells relative to the normal cells, especially compounds 7i and 7l. Besides, in-vivo toxicity assessment revealed that compound 7l increased life-span prolongation of the EAC-bearing mice group and reduced the volume and EAC cells count in animal models.

Conclusion: Accordingly, the afforded 5-oximidazoline-sulfadiazine hybrids represent promising lead candidates for further optimization to obtain promising anticancer agents.

Benzimidazole derivatives represent a versatile class of compounds in anticancer drug development due to their unique fused bicyclic structure comprising benzene and imidazole rings. The derivatives are engineered to include various chemical modifications, where in most cases, they include other heterocyclic rings or pharmacophores which augment their biological activities and specificity to cancer cells. These anticancer effects are complex and encompass Tubulin polymerization inhibition, DNA intercalation, topoisomerases I and II suppression, apoptotic pathway modulation, and inhibition of major tumor suppressor kinases that include the MAPK and PI3K/AKT. Such activities interfere with the growth of cancer cells, cause cell cycle arrest, induce apoptosis, and prevent angiogenesis and metastasis. Their in vitro antitumor and in vivo efficacies that include the ability to be used to treat a variety of tumor cell lines in preclinical studies are affirmed by their cytotoxicity and have potential pharmacokinetic and safety profiles. This group of compounds have great clinical potential in the form of targeted therapeutics because of structural flexibility making them useful in precision medicine. Their progression into a clinically useful anticancer drug remains investigating of their structure-activity relationship and molecular docking studies, with benzimidazole derivatives being some of the possible real-life solutions against cancer.

Aim: Antibiotic resistance is a critical global health challenge, with many pathogens developing mechanisms to evade current treatments, resulting in rising mortality from once-manageable infections. Superbugs such as methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacterales (CRE), and multidrug-resistant Pseudomonas aeruginosa are classified as urgent threats by the Centers for Disease Control and Prevention (CDC). This growing resistance underscores the urgent need for new antibacterial agents. In this study, pyrazole - pyrimidine hybrids linked to piperazine urea derivatives were explored to identify promising antibacterial scaffolds.

Materials and methods: A series of ten pyrazole-pyrimidine-piperazine urea hybrids (U1-U10) were synthesized through a multi-step process and evaluated against six clinically relevant bacterial pathogens: Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecium, and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined, and molecular docking against Serine hydroxymethyltransferase (SHMT) was performed..

Results and conclusion: Several compounds displayed moderate antibacterial activity, with notable inhibition of E. faecium, including vancomycin-resistant strains. Derivatives bearing cyclopropyl (U4) and benzonitrile (U8) substituents exhibited significant activity against E. faecium and S. aureus (MIC = 100 µg/mL). Molecular docking revealed favorable binding through hydrogen bonding and hydrophobic contacts with key SHMT residues. This study identifies U4 and U8 as superior antibacterial candidates, suggesting rigid hydrophobic and electron-withdrawing substituents enhance antibacterial potency.

Aims: To biologically evaluate a series of hydrazide derivatives of mefenamic acid as anti-urease agents, elucidating their mechanism of action through integrated computational and experimental approaches.

Method: The inhibitory mechanism was interpreted through comprehensive computational studies: molecular docking to identify binding modes within the catalytic site of H. pylori urease (PDB: 4UBP), Density Functional Theory (DFT) calculations to evaluate global chemical reactivity and frontier molecular orbitals (FMOs), and Molecular Dynamics (MD) simulations to confirm complex stability. Preliminary pharmacokinetic and toxicity profiles were predicted in silico.

Results: Compound 2a, featuring a para-nitro substituent, emerged as the most potent inhibitor (IC₅₀  = 21.33 ± 0.01 µM), outperforming the standard thiourea (IC₅₀  = 22.36 ± 0.30 µM).

Discussion: DFT analysis revealed 2a possessed the lowest energy gap (Δε = 2.417 eV) and highest electrophilicity index (ω = 8.658 eV), correlating with superior reactivity and charge-transfer capacity. Molecular docking confirmed competitive inhibition with 2a forming key hydrogen bonds with Arg339 and His323.

Conclusion: This work identifies 2a as a potent, and competitive urease inhibitor. The integrated experimental, ADMET and computational strategy provides a robust molecular blueprint for its activity, positioning it as a promising lead candidate for developing new therapeutic agents against urease-related pathologies.

Indole derivatives constitute a structurally heterogeneous and clinically promising class of anticancer agents. Notably, their biological activity stems from targeting multiple hallmarks of cancer, including dysregulated proliferation, apoptotic evasion, angiogenesis, and epigenetic perturbations, the key processes that drive malignant progression. The indole framework facilitates ready structural modification, enabling specific binding to cancer-selective molecular targets. By comparison, pyrimidine derivatives owe their capacity to act as "molecular mimics" or enzyme inhibitors to their structural analogy to endogenous pyrimidines, which allows them to capitalize on cancer-specific vulnerabilities. Thus, the rational hybridization of indole and pyrimidine scaffolds represents a promising strategy for the development of novel and potent anticancer therapeutics. The present work aims to summarize the current landscape of indole-pyrimidine hybrids with anticancer potential, covering articles published from 2021 to date. The structure-activity relationships and the mechanisms of action are also discussed for further rational design of novel anticancer drug candidates.

Introduction: A series of substituted indole derivatives have been synthesized and evaluated for their atypical antipsychotic activity Compared to traditional neuroleptics, second-generation or "atypical" antipsychotics offer a more favorable therapeutic profile against both positive and negative symptoms of schizophrenia.

Methods: The compounds were designed based on their physicochemical similarity studies to standard drugs and in silico (docking studies) with 5-HT_2A and D₂ receptors. The prepared compounds were evaluated for atypical antipsychotic activity in animal models of dopaminergic (apomorphine-induced mesh climbing behavior and stereotypy) and serotonergic antagonism (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI) induced head twitch assay). All the test compounds showed. The potential of these compounds to penetrate the blood-brain barrier (log BB) was computed through an online software program, and the values obtained for the compounds suggest good potential for brain permeation.

Results: In-silico (docking studies) suggested good binding of the test compounds to the 5-HT_2A and D₂ receptors and a hypothetical binding model for the target compounds was postulated. The prepared test compounds, designated as 8 to 15, exhibited an atypical antipsychotic profile in the pharmacological assays with a mechanistic profile of combined 5-HT_2A and D₂ antagonism.

Conclusion: The study has afforded novel indole-based lead molecules with potential atypical antipsychotic effect.

Aim: A novel series of Pyridine-Quinazoline-Oxadiazole hybrid analogs was synthesized as potential inhibitors of maternal embryonic leucine zipper kinase (MELK) with anticancer activity.

Method: The synthesized compounds were confirmed structurally using ¹H, ¹³C NMR, and mass spectrometry. Anticancer activity was evaluated in SK-OV3 ovarian cancer cells with the MTT assay. The effects on cell cycle and apoptosis were examined using flow cytometry. MELK inhibition was assessed through an enzyme assay.

Result: Compound 14j exhibited strong anticancer effects, with an IC₅₀ of 1.53 ± 0.04 µM, compared to doxorubicin, which had an IC₅₀ of 14.38 ± 0.10 µM in a concentration-dependent manner. Additionally, the MELK enzyme assay for 14j exhibited the strongest inhibition (IC₅₀ = 78 ± 0.47 nM), versus doxorubicin (IC₅₀ = 178 ± 0.66 nM). Furthermore, mechanistic studies on 14j revealed cell cycle at the G1/G2 phase, induction of apoptosis, and only 3.5% cell viability. The molecules also showed notable antioxidant potency. Moreover, molecular docking and dynamics simulations revealed a stable binding conformation within the MELK active site. In-silico ADMET profiling yielded better results regarding pharmacokinetic behavior and stability.

Conclusion: The synthesized Pyridine-based hybrids exhibit potent MELK inhibition, promising anticancer activity, and favorable in-silico drug profiles. 14j emerged as strong lead candidate for further anticancer drug development.

Aims: In this study, α-aminophosphonates and oxazaphosphinanes were synthesized and evaluated for their potential anticancer activity. The objective was to assess their cytotoxic effects against various cancer cell lines and to investigate their molecular interactions with cancer-related targets.

Materials and methods: The synthesized compounds were tested in vitro against four human cancer cell lines: HCT116 (colon), A549 (lung), PC3 (prostate), and MCF-7 (breast). Cytotoxicity was assessed through IC₅₀ determination. Molecular docking was performed on cyclin-dependent kinase 2 (CDK2) and anaplastic lymphoma kinase (ALK), followed by 300 ns molecular dynamics (MD) simulations for the most active compounds. Density functional theory (DFT) calculations were conducted to analyze electronic properties and reactive functional sites.

Results: Most compounds showed moderate to good anticancer activity, with IC₅₀ values ranging from 28.8 to 242.0 µM. Docking studies revealed strong binding affinities toward ALK (-6.23 to -8.46 kcal/mol) and CDK2 (-6.60 to -8.14 kcal/mol). Compounds 9b and 10c demonstrated the most favorable activity, exhibiting stable interactions in MD simulations and distinct electronic profiles in DFT analyses.

Conclusions: The integrated experimental and computational results identify compounds 9b and 10c as promising lead candidates for further development as potential anticancer agents.