Future medicinal chemistry最新文献

Aim: Novel hybrids of ibuprofen and naproxen were designed as dual COX-2/5-LOX inhibitors to create safer anti-inflammatory drugs.

Materials and methods: The prodrugs were developed through a hybridization molecular approach; their potency against COX-1, COX-2, and 5-LOX was assessed, alongside measurements of PGE2 levels, NO scavenging, and mTOR and Nrf2 protein expression. Molecular docking was used to predict binding interactions.

Results: Hybrids 9 and 10 showed excellent COX-2 inhibition with IC₅₀ values of 3.3 and 2.0 µM, respectively, and high selectivity indices (SI) of 20.7 and 17.2. Both hybrids also demonstrated substantial 5-LOX inhibition with IC₅₀ values of 3.1 and 4.2 µM.

Conclusion: The new hybrids exhibit strong COX-2/5-LOX inhibition, suggesting their structural framework is crucial for developing safer anti-inflammatory drugs.

Aim: We aimed to design and synthesize novel pyrimidine-2-thione derivatives (1-13) as Topoisomerase I/II (Topo I/II) inhibitors with DNA intercalation potential for cancer treatment.

Materials & methods: Inhibitory concentration 50 (IC₅₀) against mammary gland breast cancer, hepatocellular carcinoma, and colorectal carcinoma was determined for all compounds. The frontier candidates (2, 6, 9, 10, and 11) were evaluated for their DNA-binding ability, Topo I, and Topo II inhibiting potential. Moreover, cell cycle and apoptosis analysis were carried out.

Results: Compound 2 displayed the best DNA-binding affinity with an IC₅₀ value of 37.24 µM in comparison to doxorubicin (Dox). Both compounds 2 and 9 showed superior nanomolar Topo I inhibitory potential, compared to Dox. Similarly, compounds 2 and 9 achieved better Topo II inhibition, exceeding that of Dox. It was revealed that compound 9 halted the cell cycle at both the P1 and G2 phases. In addition, compound 9 was able to boost the apoptosis at both the early and late apoptotic phases.

Conclusion: Consequently, the compounds afforded can be regarded as prominent lead anticancer compounds for further optimization and investigation.

Aim: A novel series of oxadiazole-based derivatives was designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors.

Method: The synthesized compounds were evaluated for their cytotoxic and VEGFR-2 inhibition activities.

Results: Compound 11i was a super cytotoxic member, showing IC₅₀ of 3.26 and 5.11 µM, twice as active as sorafenib (IC₅₀ = 8.83 and 6.68 µM) against hepatocellular carcinoma (HepG2) and colon cancer (HCT-116), respectively. Also, the VEGFR-2 inhibitory assay revealed that derivative 11_i was the most potent VEGFR-2 inhibitor, showing a strong IC₅₀ value of 0.56 nM, compared to sorafenib (IC₅₀ = 0.46 nM). Furthermore, extra mechanistic studies were conducted on the most active candidate 11_i. The results indicated that such a compound arrested the cell cycle at both S and G2/M stages, triggering apoptosis in HepG2 cells. Also, compound 11_i produced a significant increase in the expression levels of apoptotic suppressors, caspase-3 and BAX, and a significant reduction of apoptosis motivator, Bcl-2 protein. Moreover, docking and molecular dynamics (MD) simulation studies revealed the correct binding mode and the optimum dynamics of compound 11_i inside the VEGFR-2 pocket.

Conclusion: This study represents compound 11_i, incorporating an oxadiazole scaffold as a promising VEGFR-2 inhibitor with potent anticancer activity.

Cancer therapy is still hampered by key challenges, including drug resistance, poor target selectivity, and narrow therapeutic spectra, driving the pursuit of novel anticancer agents with enhanced efficacy and safety. Indole-triazole/pyrazole hybrids, formed by fusing indole scaffolds with triazole/pyrazole, confer inherent structural diversity and high modifiability. Structurally, rational modification of indole/triazole/pyrazole moieties allows optimization of pharmacokinetic properties and improves cancer cell selectivity, minimizing toxicity to normal cells. Functionally, indole-triazole/pyrazole hybrids exhibit multitargeted activity to simultaneously inhibit key oncogenic pathways, addressing the heterogeneity of cancer pathogenesis, while their hybrid structure enhances anticancer potency. This multitargeted mode also aids in overcoming drug resistance, a major bottleneck in clinical therapy. Accordingly, indole-triazole/pyrazole hybrids have emerged as a promising class of anticancer candidates. This review summarizes recent advances in indole-triazole/pyrazole hybrids with anticancer potential, covering articles published from 2021 to the present. To delineate the key molecular features governing anticancer potency, this review further presents a detailed analysis of structure-activity relationships (SARs) and conducts an in-depth exploration of the underlying mechanisms of action.

Liver cancer, which originates from hepatocytes, ranks among the most commonly diagnosed cancers and stands as a leading cause of cancer-related deaths, primarily due to late diagnosis and its rapid progression. Liver cancer, especially metastatic liver tumors, often relies on chemotherapy. Still, drug resistance driven by the overexpression of efflux pumps, reduced systemic drug exposure due to hepatic metabolism, low efficacy, and high toxicity creates an urgent need to explore novel chemotherapeutic agents. Hydroxamic acid serves as the zinc-binding group (ZBG) in most histone deacetylase (HDAC) inhibitors and is an important anti-liver cancer pharmacophore. Hydroxamic acid hybrids harness the epigenetic potency of hydroxamic acid through modular pharmacophore integration, providing multitarget efficacy, resistance overcoming, and therapeutic versatility, and thus represent promising candidates for next-generation liver cancer therapies.

Aim: To design and synthesize novel dihydropyrimidinone-pyrazole hybrid compounds as potent and selective antitumor agents, exploring their potential mechanism of action.

Materials & methods: A series of target compounds were synthesized and evaluated for their in vitro antiproliferative activity against three human cancer cell lines: A549 (lung adenocarcinoma), MIA PaCa-2 (pancreatic carcinoma), and HepG2 (hepatoblastoma). Cytotoxicity was also assessed in non-cancerous Vero cells, along with an in vivo acute toxicity evaluation in mice. The metabolic stability of the lead compounds was investigated using human liver microsomes. Potential molecular targets were identified through in silico prediction, and the proposed mechanism was further validated via molecular docking, molecular dynamics (MD) simulations, and enzymatic inhibition assays.

Results: Compounds 14 and 27 demonstrated potent, broad-spectrum antiproliferative activity in the submicromolar range, exhibiting high selectivity indices against cancer cells and favorable metabolic stability. Integrated computational and enzymatic studies identified Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) as a potential molecular target, suggesting that the antitumor activity may be mediated through its inhibition.

Conclusion: Compounds 14 and 27 are established as promising anticancer candidates worthy of further development. Future work will focus on comprehensive in vivo efficacy studies and deeper mechanistic investigation to advance this novel chemical series.

Aims: To evaluate chromatographic lipophilicity of novel artesunate-pyrimidine hybrids and precursors using reversed-phase thin-layer chromatography (RP-TLC) and assess plasma protein binding (PPB). The impact of measured and predicted lipophilicity on pharmacokinetic descriptors was evaluated. Principal component analysis (PCA) explored relationships among lipophilicity, PPB, and physicochemical descriptors. Quantitative structure-activity relationship (QSAR) and partial least squares (PLS) models linked molecular descriptors to cytotoxicity and resistance modulation in nonsmall cell lung cancer (NSCLC) cells.

Materials and methods: Lipophilicity was measured by RP-TLC. PPB was determined using human serum albumin (HSA)-modified high-performance liquid chromatography (HPLC). PCA characterized physicochemical-pharmacokinetic correlations. Cytotoxicity in sensitive NCI-H460 and multidrug-resistant (MDR) NCI-H460/R cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. QSAR and PLS models identified key descriptors.

Results: Lipophilicity strongly influenced adsorption, distribution, and protein binding. Highly lipophilic hybrids showed near-complete HSA binding. Compound 2k lost cytotoxicity in the presence of albumin, whereas 4k retained potency. Models indicated steric and electronic features, alongside lipophilicity, dictate efficacy and P-glycoprotein (P-gp) interactions, particularly in resistant cells.

Conclusions: Lipophilicity and steric/electronic descriptors govern distribution, protein binding, and anticancer activity. Integrating these features enables design of hybrids overcoming P-gp-mediated multidrug resistance, with hybrid 4k emerging as a promising candidate.

Autophagy is an evolutionarily conserved process in eukaryotic cells that degrades and recycles intracellular macromolecules and damaged organelles. It is closely related to a variety of physiological and pathological processes. Research on autophagy has become a current hotspot, with protein kinases regarded as crucial components that play essential roles throughout this process. During autophagy, diverse autophagy-related protein kinases continuously regulate different stages. Protein kinases are critical in signal transduction and the regulation of most cellular processes. Therefore, autophagy-associated protein kinases represent potential therapeutic targets for human diseases, and corresponding small-molecule compounds may provide promising therapeutic strategies. This review summarizes the current progress in autophagy research, with a focus on small-molecule drugs that influence autophagy-related kinases and their association with diseases.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer that remains incurable because it is often detected at an advanced stage, making treatment difficult.

Martials and methods: The reaction of free metformin (5) with isothiocyanate derivatives (6-9) and the or with 4-toluenesulfonyl isocyanate (10) afforded the targeted metformin analogues (11-15). The in vitro anticancer impact of these compounds was assessed using cell lines of BJ1, PACA2, and HePG2.

Results: Compound 13 had significant cytotoxic effects against PACA2 and HePG2 with mortality 88.30% and 71.20%, respectively. In a chronic study, the body weights of male rats receiving 13 at a dose of 50 mg/kg for 12 consecutive weeks showed an insignificant difference in the percentage change in body weight. Histopathological examination of the pancreas and liver with 13 exhibited normal histological structure of exocrine and endocrine parts. Additionally, normal cardiac myocytes were observed in the heart of rats treated with 13.

Conclusions: It can be inferred that the daily administration of 50 mg/kg of compound 13 over a duration of 12 weeks did not elicit any substantial alterations in body weight, biochemical, hematological, or histopathological parameters, while concurrently exhibiting pronounced anticancer efficacy against pancreatic ductal adenocarcinoma (PDAC).