Future medicinal chemistry最新文献

MMP-2 is crucial for ECM remodeling and embryonic development. MMP-2 is a key biomolecular target for its strong association with cancer progression, metastasis, and angiogenesis. Again, the implication of MMP-2 in other diseases is well-established. Though several MMPIs failed after extensive clinical studies due to a lack of selectivity, poor pharmacokinetics, and dose-related toxicities, there is still a huge opportunity to develop specific MMP-2 inhibitors to battle against such life-threatening diseases as cardiovascular diseases, diabetes, renal diseases, and inflammatory diseases. Here, the development of small-molecule MMP-2 inhibitors for the last five years, comprising various ZBGs and diverse scaffolds, as well as their structural information along with their in-depth biological implications in cancers and other diseases, has been discussed in detail. This study may reinforce the importance of potential and selective MMP-2 inhibition as a therapeutic approach, paving the way for future research into optimizing small-molecule MMP-2 inhibitors for clinical applications. As the development of these MMP-2 inhibitors advances, further in vivo studies and structure-activity relationship optimizations will be essential to translate these promising results into viable therapeutic options for several cancers and other life-threatening diseases.

Introduction: Cancer is one of the predominant causes of mortality globally. Radiation, surgery, and chemotherapy are currently available methods for treating cancer. Each of these approaches has known adverse effects. Due to their better efficacy and safety over traditional chemotherapy drugs, targeted therapeutic medicines are quickly becoming standard cancer treatments.

Areas covered: Small molecules have several advantages, such as being able to be given orally and having the capacity to pass through cell membranes and enter intracellular spaces. This review is going to focus on small molecules as anticancer scaffolds and researchers will be able to design new antineoplastic compounds in the future on the basis of the thoroughly discussed SAR investigation, preclinical data, clinical outcomes, and FDA approved molecules.

Expert opinion: Since there is currently no cure for most forms of disseminated cancer, the development of novel active chemotherapeutic drugs is essential. Small molecules are interesting drug candidates as they are able to target important molecular pathways with selectivity. An in-depth analysis of the SAR study and the available preclinical and clinical data can greatly assist in the development of the next generation of anticancer drugs that would be more potent, selective, and would interfere with fewer side effects.

Functioning as a critical regulatory enzyme within the mitogen-activated protein kinase (MAPK) cascade, BRAF kinase orchestrates fundamental biological mechanisms while exhibiting high mutation prevalence in malignant pathologies, including cutaneous melanoma and colorectal adenocarcinoma. While selective BRAF inhibitors show efficacy, their use is hampered by drug resistance and compensatory pathway activation. Dual-target inhibitors, which simultaneously block BRAF and another oncogenic target, offer a promising strategy to enhance therapeutic effects, reduce resistance, and minimize off-target toxicity. These drugs synergistically disrupt compensatory mechanisms, demonstrating robust antitumor activity in preclinical models. This review highlights the structural characteristics and functional roles of BRAF kinase, elucidating its significance in disease pathogenesis and therapeutic targeting. Furthermore, it investigates emerging trends in pharmacological intervention strategies, particularly focusing on the advancement and clinical potential of dual-target therapeutic approaches within the framework of modern drug discovery. Through critical analysis of recent developments, the discussion extends to evaluating challenges and opportunities in designing multi-target agents from a molecular design standpoint.

Aim: Synthesisof 3-aminowithaferin A and its imine congeners to identify promising lead molecules for future development as anti-cancer agents.

Materials and methods: 3-Aminowithaferin A was synthesized through aza-Michael addition using liquid ammonia as a nucleophile. In order to obtain imine congeners various aldehydes were allowed to undergo addition-elimination with 3-aminowithaferin A. All the newly synthesized compounds were screened for their cytotoxicity against eight cancers and one normal cell line using MTT assay.

Results and conclusion: One of the imine analogs, referred to as compound 13, exhibited significant antiproliferative and anti-metastatic properties across various cell lines, particularly in triple-negative breast cancer lines, with an IC50 value ranging from 507 nM to 2.475 µM. Compound 13 effectively inhibited the formation of invadopodia and filopodia, underscoring its anti-invasive properties. Additionally, immunoblotting studies demonstrated a consistent decrease in the expression of various epithelial-to-mesenchymal transition (EMT) markers in the presence of compound 13, further confirming its anti-metastatic properties.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor that regulates the expressions of a variety of target genes related to glucose homeostasis. It has been recognized that PPARγ is a druggable target in modern drug discovery. In this review, the design of synthetic PPARγ agonists, and the development of synthetic PPARγ agonists of diverse scaffolds including thiazolidinediones (TZDs) and non-TZDs were illustrated. In addition, the recent advances and the therapeutic applications of reported synthetic PPARγ agonists were discussed including type 2 diabetes (T2DM), liver and inflammatory diseases, cancer, and neurological disorders within the past ten years using cellular and animal models and clinical studies. Our aim is to promote PPARγ agonists as a promising breakthrough point for addressing the therapy of different human disorders by inspiring additional scientific communities.

Aim: The chalcone scaffold pyrazole is important in organic and medicinal chemistry. This study presents the design and synthesis of new chalcone-coupled pyrazole derivatives (1a-1o). The new compounds were characterized using FT-IR, ¹H-NMR, ¹³C-NMR, GC-MS, elemental analysis, and cytotoxic analysis on MCF-7 and HepG2 cancer cell lines. The synthesized compounds also underwent molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and DFT (density functional theory) studies.

Results: Compound 1a showed high cytotoxic activity against MCF-7 cells (LC₅₀, 0.62 ± 0.01 µM), outperforming standard Doxorubicin. Compounds were examined using molecular docking, ADME-T, and DFT calculations. Compound 1a had a higher binding affinity (-10.8 Kcal/mol) than Doxorubicin (-4.7 Kcal/mol). ADME-T profile and pharmacokinetic predictions were performed on the analogs. DFT with the B3LYP/6-311++G (DP) basis set helped determine optimal shape and dimensions. Additional Gaussian 16-based DFT calculations were conducted on compounds (1a-1o). The HOMO-LUMO analysis revealed compound 1a had a significant energy gap (2.5056 eV, from -7.94026 eV to -5.43465 eV).

Conclusion: Compound 1a may be a promising anti-cancer agent.

Aims: This study aimed to design, synthesize, and evaluate a novel series of pyridine-linked thiazolidinone analogues (1-15) as dual inhibitors of thymidine phosphorylase and α-glucosidase, with potential therapeutic applications in diabetes mellitus and cancer-related angiogenesis.

Materials & methods: The compounds were synthesized through a multistep reaction pathway and characterized by spectroscopic techniques. Their inhibitory activities were assessed against α-glucosidase and thymidine phosphorylase using in vitro enzyme assays. Molecular docking studies were performed to elucidate binding interactions, while ADMET analysis predicted pharmacokinetic properties. Enzyme kinetics studies were conducted to determine the mode of inhibition.

Results: The synthesized analogues displayed strong inhibitory activity, with IC₅₀ values ranging from 2.10 ± 0.20 to 19.10 ± 0.20 µM against α-glucosidase and 3.10 ± 0.20 to 19.80 ± 0.10 µM against thymidine phosphorylase. Several compounds demonstrated superior potency compared to standard drugs, including compound 2 (IC₅₀ = 2.10 ± 0.20 µM for α-glucosidase; 3.10 ± 0.20 µM for thymidine phosphorylase). Docking and ADMET analyses confirmed favorable drug-like properties, while kinetic studies revealed competitive inhibition at low concentrations.

Conclusions: The pyridine-linked thiazolidinone analogues represent promising dual inhibitors with potential as therapeutic leads for diabetes mellitus and thymidine phosphorylase-associated disorders.

Aims: This study investigates the inhibitory potential of a novel series of thioflavonol derivatives (1-12) against α-glucosidase, a key biological macromolecule involved in carbohydrate metabolism, to identify new candidates for type 2 diabetes therapy.

Materials and methods: The compounds were evaluated using in vitro enzyme inhibition assays, followed by in vivo antihyperglycemic studies of the most active derivatives. Enzyme kinetics determined the inhibition mechanism, while SAR analysis elucidated structural features governing activity. Computational studies, including molecular docking (PDB IDs: 5NN8 and 8CB1), molecular dynamics simulations, and DFT calculations, explored binding modes and electronic properties. ADMET profiling assessed drug-likeness.

Results: Several derivatives exhibited strong α-glucosidase inhibition, with the most active compound significantly lowering blood glucose levels in vivo. SAR analysis highlighted key substituents contributing to potency. Docking and MD simulations revealed stable enzyme - inhibitor complexes, and DFT supported favorable electronic interactions.

Conclusions: This is the first comprehensive study of thioflavonols as α-glucosidase inhibitors, demonstrating their promising biological activity, stable binding behavior, and favorable pharmacokinetic properties, supporting their potential as novel anti-diabetic agents.

Aims: Development of two regioisomeric sets of polyether-linked bis-hydrazothiazole derivatives that could be used as anticancer prototypes.

Materials and methods: Two construction scaffolds, bis-phenacyl bromide 4 and bis-thiosemicarbazones 6a,b were utilized as efficient building blocks to access desired bis-hydrazothiazole derivatives 8a-l and 10a-l. These bis-thiazoles were screened against four different cancer cell lines - liver (HepG-2), lung (A-549), colorectal (HCT-116), and prostate (PC-3). Computational simulations of the most potent bis-hydrazothiazoles using molecular docking assessment (RMSD, 1.15 Å) were utilized to support in vitro experimental findings.

Results: The new bis-thiazoles 8a-l and 10a-l showed varying levels of mild to good cytotoxicity, with chloro-substituted derivatives 8c, 8i, 10c, and 10i showing notable cytotoxicity and selectivity against liver carcinoma with IC₅₀: 10.3, 12.2, 23.9, and 11.1 µM, respectively. Cell cycle arrest is propelled by inducing total apoptosis from 0.18% for the untreated control cells to 18.63, 28.13, 35.68, and 16.07% for bis-thiazoles 8c, 8i, 10c, and 10i, respectively. Molecular docking showed the ability of the most potent bis-hydrazothiazoles 8c, 8i, 10c, and 10i to inhibit Pim-1 kinase.

Conclusions: Two novel regioisomeric sets of polyether-linked bis-hydrazothiazoles were developed. These new bis-heterocycles have been proven to be highly selective anticancer prototypes against HepG2 carcinoma.