Medicinal Chemistry最新文献

Aim: There is an urgent need for new antimicrobial compounds with alternative modes of action for the treatment of drug-resistant bacterial and fungal pathogens.

Background: Carbohydrates and their derivatives are essential for biochemical and medicinal research because of their efficacy in the synthesis of biologically active drugs.

Objective: In the present study, a series of methyl α-D-mannopyranoside (MMP) derivatives (2-6) were prepared via direct acylation, and their biological properties were characterized.

Methods: The structures of synthesized compounds were established by analyzing their physicochemical, elemental, and spectroscopic data and evaluating their in vitro antimicrobial activities through in silico studies.

Results: In the antibacterial study, compound 3 was found to be mostly active toward most of the organisms, exhibiting maximum inhibition of S. abony and minimum inhibition of P. aeruginosa. However, the MIC and MBC values revealed that this compound is highly effective against Bacillus subtilis (MIC of 0.5 μg/L and MBC of 256 μg/L). In terms of antifungal activity, 3 and 6 showed the most promising activity toward Aspergillus flavus, with an inhibition of 95.90 ± 1.0% for compound 3 and 96.72 ± 1.1% for compound 6. Moreover, density functional theory (DFT) in conjunction with the BLYP/6-311G (d) basis sets was used to calculate the dipole moment and total energy for each compound, and the molecular electrostatic potential and Mulliken charge were considered to study the electrophilicity and nucleophilicity of the groups in each compound. For dipole moment calculations, the dipole moments are in the following order: 6 < 3 < 1 < 5 < 2 < 4, inferring that compounds 2 and 4 possess a high dipole moment in comparison with the other inhibitor systems. Furthermore, molecular docking was performed against threonine synthase from B. subtilis ATCC 6633 (PDB: 6CGQ) to identify the active site of the compounds, with compound 3 showing a maximum binding energy of -10.3 kcal/mol and compound 4 exhibiting a binding energy of -10.2 kcal/mol. In addition, a 100 ns MD simulation was performed, and the results revealed a stable conformation and binding pattern within the stimulating environment.

Conclusion: Our synthetic, antimicrobial, and in silico experiments revealed that MMP derivatives exhibit potential activity, providing a therapeutic target for bacteria and fungi.

Background: This work presents the synthesis of Ru(II)NHC complexes bearing a series of 4-fluorobenzyl group. These complexes have been characterized by a variety of spectroscopic methods (¹H NMR, ¹³C NMR, and FTIR) and by elemental analysis techniques.

Methods: These complexes' antitumor activities against SH-SY5Y (human neuroblastoma) and HCT116 (human colon cancer) were investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assay.

Results: The results showed that all the synthesized complexes exhibited significant cytotoxic effect with low IC₅₀ values 15 ± 0.57, 15.26 ± 0.71, 7.64 ± 0.30, 27.66 ± 0.36 and 14.45 ± 0.84 (μg/mL) respectively.

Conclusion: Furthermore, apoptosis assessed by double labeling with Annexin V-FITC/PI indicated that complexes 1b and 1d can effectively induce apoptosis and inhibit cell proliferation at the S phase in SH-SY5Y cells. Taken together, Ru(II)NHC complexes containing the 4- fluorobenzyl group have significant potential for the development of novel, highly effective anticancer agents.

Introduction: SYK (Spleen Tyrosine Kinase) regulates immune response and is a promising target for cancer, sepsis, and allergy therapies. This study aims to create novel compounds that serve as alternative inhibitors for cancer treatments targeting SYK.

Methods: A thorough combination of machine learning (ML) and physics-based methods was employed to achieve these goals, encompassing de novo design, multitier molecular docking, absolute binding affinity computation, and molecular dynamics (MD) simulation.

Results: A total of 5576 novel molecules with key pharmacophoric features were generated using an ML-driven de novo approach against 21 diaminopyrimidine carboxamide analogs. Pharmacokinetic and toxicity evaluation assisted by the ML approach revealed that 4353 chemical entities fulfilled the acceptable pharmacokinetic and toxicity profiles. By screening through binding energy threshold from the physics-based multitier molecular docking, and ML-assisted absolute binding affinity identified the top four molecules such as RI809 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((2- aminocyclohexyl)oxy)benzamide), RI1393 (4-((2-aminocyclohexyl)amino)-2-(3-(1-methyl-1Hpyrazol- 5-yl)-4-(trifluoromethyl)benzyl)benzamide), RI2765 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((4- aminocyclohexyl)methyl)benzamide), and RI3543 (2-([1,1'-biphenyl]-2-ylmethyl)-4-(piperidin-3- yloxy)benzamide). The final molecules identified exhibit a strong affinity for SYK, attributed to their structural diversity and notable pharmacophoric characteristics. All-atom MD simulations showed that each final molecule retained significant binding interactions with SYK and stability in dynamic states, indicating their potential as anticancer agents. Calculated binding free energy for selected molecules using molecular mechanics with generalized Born and surface area (MMGBSA) ranged from -6 to -35 kcal/mol, indicating strong SYK affinity.

Conclusion: In conclusion, the integration of AI and physics-based methods successfully developed promising SYK inhibitors with significant potential. The molecules reported could be vital anticancer agents subjected to experimental validation.

The five-membered oxazole motif heterocyclic aromatic ring has been gaining considerable attention due to its bioisosterism property and unusually wide range of desired biological properties. Thus, it is a perfect pre-built platform for the discovery of new scaffold development in medicinal chemistry. In recent years, the potential of oxazoles has garnered significant attention from medicinal chemists, resulting in the development of several synthetic and plant-based drugs currently in the market. Interest in the biological applications of oxazoles has notably intensified over the past fifteen years. This overview aims to provide a comprehensive, systematic summary of recent advancements in the synthetic chemistry of oxazole-based compounds, highlighting significant progress in their biological applications during this period as well as outlining prospects for further development. In summary, we overview literature in synthetic chemistry and explore structure- activity relationships and mechanisms of action with medicinal applications for the development of oxazole derivatives that hold promise for discovering new and effective drug candidates.

Background: Neurodegenerative diseases are a group of disorders characterized by progressive neuronal degeneration and death, of which Alzheimer's disease and Parkinson's disease are the most common. These diseases are closely associated with increased expression of monoamine oxidase B (MAO-B), an important enzyme that regulates neurotransmitter concentration, and its overactivity leads to oxidative stress and neurotoxicity, accelerating the progression of neurodegenerative diseases. Therefore, the development of effective MAO-B inhibitors is important for the treatment of neurodegenerative diseases.

Objective: This study aims to improve the prediction of the efficacy of novel 6-hydroxybenzothiazole- 2-carboxamide compounds in inhibiting MAO-B by improving the quantitative constitutive effect relationship (QSAR) modeling and to provide a theoretical basis for the discovery of novel neuroprotective drugs.

Methods: The study first optimized the structures of 36 compounds using the heuristic method (HM) in CODESSA software to construct linear QSAR models. Subsequently, key descriptors were screened by using the gene expression programming (GEP) technique to generate nonlinear QSAR models and validate them.

Results: The R², F-value, and R²cv of the linear model were 0.5724, 10.3752, and 0.4557, respectively, whereas the nonlinear model constructed by the GEP algorithm showed higher prediction accuracies by achieving R² values of 0.89 and 0.82, and mean squared errors (MSE) of 0.0799 and 0.1215 for the training and test sets, respectively. In addition, molecular docking experiments confirmed that the novel compound 31 was tightly bound to the MAO-B active site with significant inhibitory activity.

Conclusion: In this study, we successfully improved the prediction ability of the efficacy of novel 6-hydroxybenzothiazole-2-carboxamide compounds to inhibit MAO-B by improving the QSAR model. This not only provides new drug candidates for the treatment of neurodegenerative diseases, but also provides important theoretical guidance for subsequent drug design and development, which can help accelerate the process of new drug discovery and reduce the disease burden of patients.

Introduction: Casein Kinase 2 (CK2), discovered as one of the earliest protein kinases, is a ubiquitous Ser/Thr protein kinase-specific to acidic environments. CK2 has been implicated in regulating diverse cellular processes and has been linked to the onset of various diseases, including cancer.

Methods: Consequently, modulating CK2 function has emerged as a potential therapeutic strategy. However, currently, available CK2 inhibitors or modulators often lack sufficient specificity and potency.

Results: The results were validated through QSAR of curcumin derivatives, Pharmacophore modeling, virtual screening performed for filtered curcumin-like featured derivatives from the database, and Molecular Docking approaches. Since there is a solved crystal structure of high-resolution Xray crystal structures of Human protein kinase CK2 alpha in complex with ferulic aldehyde.

Conclusion: Also, structure-based virtual screening was performed against a total of 3253 compounds from different libraries, and only the top 4 best-hit compounds with exceptional docking scores exceeding > -7 kcal/mol (more than 7 kcal/mol) were screened and analyzed. However, to validate their therapeutic potential, these compounds require in-vitro evaluation to assess their CK2 targeting ability.

Introduction: Breast cancer remains a formidable health concern for women, necessitating the development of potent anticancer agents with improved safety profiles. Dihydropyrimidinones (DHPM), pyrazole, and benzofuran scaffolds have emerged as promising targets due to their diverse pharmacological profiles. In this study, we employed a scaffold hopping approach to design a novel DHPM-Pyrazole-Benzofuran core. A series of compounds (3a-3j) were synthesized using the Biginelli protocol, and their characterization was performed using various techniques such as FTIR, ¹H NMR, and Mass spectroscopy.

Methods: Molecular docking studies against kinesin spindle protein Eg5 (1Q0B) performed to find superior binding interactions compared to the prototype Eg5 inhibitor Monastrol. Anti breast cancer potential of these compounds was screened against the breast adrenocarcinoma MCF-7 cell line using an SRB assay.

Results: Compound 3j showed good growth inhibitory activity (GI₅₀=24.08 μM) compared to Monastrol (GI₅₀=32 μM) employed as a positive control. Moreover, Compound 3j exhibited strong interactions with amino acids GLU-116 and ARG-119 with Eg5 protein 1Q0B.

Conclusion: Compound 3j fits well at the allosteric site of Eg5 protein 1QOB. Compound 3j emerged as the most cytotoxic, displaying significant and impressive growth inhibitory activity (GI₅₀=24.08 μM).

Background: The approval of Sucrose Fatty Acid Esters (SFAEs) as food additives/ preservatives with antimicrobial potential has triggered enormous interest in discovering new biological applications. Accordingly, many researchers reported that SFAEs consist of various sugar moieties, and hydrophobic side chains are highly active against certain fungal species.

Objective: This study aimed to conduct aregioselective synthesis of SAFE and check the effect of chain length and site of acylation (i.e., C-6 vs. C-2, C-3, C-4, and long-chain vs. short-chain) on antimicrobial potency.

Methods: A direct acylation method maintaining several conditions was used for esterification. In vitro tests, molecular docking, and in silico studies were conducted using standard procedures.

Results: In vitro tests revealed that the fatty acid chain length in mannopyranoside esters significantly affects the antifungal activity, where C12 chains are more potent against Aspergillus species. In terms of acylation site, mannopyranoside esters with a C8 chain substituted at the C-6 position are more active in antifungal inhibition. Molecular docking also revealed that these mannopyranoside esters had comparatively better stable binding energy and hence better inhibition, with the fungal enzymes lanosterol 14-alpha-demethylase (3LD6), urate oxidase (1R51), and glucoamylase (1KUL) than the standard antifungal drug fluconazole. Additionally, the thermodynamic, orbital, drug-likeness, and safety profiles of these mannopyranoside esters were calculated and discussed, along with the Structure-Activity Relationships (SAR).

Conclusion: This study thus highlights the importance of the acylation site and lipid-like fatty acid chain length that govern the antimicrobial activity of mannopyranoside-based SFAE.

Objective: The objective of this study is to explore the therapeutic potential of phytochemicals in cancer cell metabolism by investigating their ability to inhibit key molecular targets involved in tumor growth and drug resistance.

Methods: We evaluated specific phytochemicals against critical cancer-related targets such as GLS1, CKα, MGLL, IDH1, PDHK1, and PHGDH. Molecular docking methods were used to understand the binding interactions between phytochemicals and their selected targets. ADME (absorption, distribution, metabolism, and excretion) analysis and molecular dynamics (MD) simulations were conducted to assess pharmacokinetic properties and ligand-protein interaction dynamics, respectively. MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) calculations were utilized to estimate binding free energies.

Results: Molecular dynamics simulations demonstrate that phytochemicals like EGCG, Diosgenin, Withaferin A, and Celastrol exhibit stable binding to their respective targets, suggesting potential therapeutic benefits. Specifically, EGCG shows strong and non-toxic binding affinity with GLS1, making it a promising candidate for cancer treatment.

Conclusion: Our study underscores the potential of phytochemicals as effective inhibitors of cancer cell metabolism. The stable binding interactions highlight promising avenues for developing innovative cancer therapies. Further experimental investigations are warranted to validate these findings and advance the development of hybrid phytochemical-based treatments for combating chemoresistance.

Introduction: Cervical cancer is a global health problem due to its high incidence and prevalence in women, mainly in third-world countries. For the treatment of this disease, there are different therapeutic options, but these are not always effective, which gives rise to the search for new compounds using cheminformatics tools.

Objective: The objective of this study was to design, synthesize, and biologically evaluate N-(2- morpholinoethyl)-2-(naphthalen-2-yloxy)acetamide hydrochloride (1) and 2-(naphthalen-2-yloxy)- N-(2-(piperidin-1-yl)ethyl)acetamide hydrochloride (2) on the HeLa cell line in vitro. The referenced cell line from the American Type Culture Collection (ATCC^®CCL-2^™) was used, and the effect on cell viability was determined by MTT metabolic reduction-based assay at 24, 48, and 72 h.

Methods: Therapies directed at the σ1 receptor may be a treatment alternative since this receptor modulates the processes of cell proliferation and angiogenesis, producing cytoprotective or cytotoxic actions depending on the ligand with which it is coupled.

Results: The analysis showed that compounds 1 and 2 presented activity on HeLa cancer cells and viability at micromolar concentrations (1.923 μmol/mL and 0.374 μmol/mL, respectively). Moreover, the effect was maintained for 72 h.

Conclusion: Naphthaleneacetamide derivatives exhibited an inhibitory effect on the HeLa cell line, and the OSIRIS program predicted less toxicity than cisplatin.