Future medicinal chemistry最新文献

The rise of antibiotic-resistant Gram-positive bacterial infections poses a significant threat to public health, necessitating the exploration of alternative therapeutic strategies. A photosensitizer (PS) can convert energy from absorbed photon into reactive oxygen species (ROS) for damaging bacteria. This photoinactivation action bypassing conventional antibiotic mechanism is less prone to resistance development, making antibacterial photodynamic therapy (aPDT) highly efficient in combating Gram-positive bacteria. Photodynamic transition metal complexes leveraging the unique properties of metals to enhance the aPDT activity are the next-generation PS. This review provides an overview of metal-based PS for combating Gram-positive bacteria. Based on the structures, these metal-PS could be mainly classified as metal-tetrapyrrole derivatives, ruthenium complexes, iridium complexes, and zinc complexes. PS based on complexes of other transition metals such as silver, cobalt, and rhenium are also presented. Finally, we summarize the advantages and shortcomings of these metal- PS, conclude some critical aspects impacting their aPDT performances and give a perspective on their future development.

Pterostilbene (PT) is a naturally occurring small molecule stilbenoid that has garnered significant attention due to its potential therapeutic effects in tumor diseases. In this review, we conducted a comprehensive analysis of the antitumor effects of PT and its derivatives on various cancer types, including colon, breast, liver, lung, and pancreatic cancers in recent 20 years. We have succinctly summarized the PT derivatives that exhibit superior anti-tumor efficacy compared to PT. Additionally, we reviewed the potential structure-activity relationship (SAR) rules and clinical application methods to establish a foundation for chemical modification and clinical utilization of stilbene compounds.

Aim: Benzimidazole-triazole conjugates are very active hotspot for design and synthesis of promising anticancer agents. The target analogs showed potent and selective cytotoxicity over different cancer cell lines for breast and lung ones.

Materials & methods: A new series of bis-1,4-disubstituted-1,2,3-triazoles moieties conjugated with a 2-mercapto-benzimidazole 4a-h and 7a-g was synthesized via the click cycloaddition (CuAAC) reaction. The synthesized triazoles were characterized using several spectroscopic tools. In addition, they were tested against variable cell lines representing different cancer types; HepG-2, MCF-7, HCT-116, and A-549. Computational experiments were introduced for understanding their structure-activity relationships.

Results & conclusion: The data revealed the outperformance of 7a-g analogs over 4a-h one with very effective IC₅₀ values; 4-13 µg/mL compared to the reference drugs. Moreover, detailed mechanistic analyses showed potent Aurora-A Kinase expression for the most active analogs 7a and 7d exhibiting IC₅₀; 3.5 and 5.3 over the control cells 8 ng/mL respectively. Additionally, based on their Aurora-A Kinase inhibitory activity, compound 7a was promising in apoptosis induction and cell cycle arrest. Molecular docking studies with Aurora-A Kinase revealed binding behaviors similar to the co-crystallized ligand sunitinib. Finally, this scaffold exhibits cytotoxic activity via apoptosis, enzyme downregulation, and suppression of cell division.

Aim: The purpose of this work was to investigate the antimicrobial activity of pyrazole derivatives (21a - i and 23a - o) synthesized.

Materials & methods: The pyrazole derivatives were synthesized, molecular docked and tested for their antimicrobial activity, cytotoxicity, and hemolysis rate.

Results: Most of the target compounds showed high selective inhibitory activity against multi-drug resistance compared with other strains. Of these, compounds 21c (MIC = 0.25 µg/mL) and 23 h (MIC = 0.25 µg/mL) showed the strongest antibacterial activity, which was 4-flods than that of the positive control compound gatifloxacin (MIC = 1 µg/mL). Furthermore, compound 23 h showed no cytotoxicity to human LO2 cells, and did not show hemolysis even at ultra-high concentration.

Conclusion: These results prompted that these compounds are valuable for further development as antimicrobial agents.

Aim: To evaluate the anti-inflammatory potential of novel class of chemical compounds designed by the linkage of carbothioamide moiety with pyridine.

Materials & methods: In silico analysis was conducted using molecular docking followed by an in vitro cytotoxicity assay and evaluation of anti-inflammatory activity. Subsequently, in vivo performance was determined using the Complete Freund's Adjuvant-induced inflammatory model, employing macroscopic, histopathological, and protein expression analyses.

Results: Molecular interaction studies revealed that compound R2 displayed the most favorable binding mode with human nitric oxide synthase, cyclooxygenase-1, and cycloxygenase-2. All compounds exhibit dose-dependent cytotoxicity. Notably, compound R4 was safer at higher concentration, whereas compound R2 was comparatively toxic. The in vitro anti-inflammatory activity demonstrated half maximal inhibitory concentration (IC₅₀) values ranging from 10.25 ± 0.0 to 23.15 ± 4.24 µM, with compound R6 exhibiting the lowest IC₅₀ value and compound R3 showing the highest. The in vivo results corroborated the anti-inflammatory effects, with a significant reduction in paw size (p < 0.001). Among the tested compounds, compound R4 exhibited the most potent anti-inflammatory activity, whereas R2 exhibited the least potency.

Conclusion: The study highlights the promise of discovering new anti-inflammatory drugs containing pyridine moiety with proven potency, efficacy, and reduced side effects.

Background: Poly(ADP-ribose) polymerase (PARP) is a superfamily of enzymes involved in cell survival. Both PARP1 and PARP14 are overexpressed in malignancies. No clinically approved PARP14 inhibitors are available, and PARP1 inhibitors are generally nonspecific, resulting in a need for a more diverse library of selective PARP1 and PARP14 inhibitors.

Materials and methods: Based on the previous lead compounds 1 and 2, 26 novel compounds were designed, synthesized, and screened against PARP1 and PARP14. Compounds with the best in vitro inhibitory results were further screened against PARP2, PARP3, PARP5a, PARP7, and PARP15.

Results and conclusion: The 26 novel compounds demonstrated a lesser inhibitory effect than the lead compounds. Compounds 1 and 2 were further investigated using in vitro cell viability assays, which revealed that cells treated with either lead PARP inhibitor and cisplatin in combination had significantly lower survival rates than those treated with cisplatin alone. At 10 µM, the combination showed more significant cell survival reduction, suggesting greater inhibition of PARP increases lethality, particularly in HeLa and PC-3 cell lines at 96 h and beyond.

Aims: This study aimed to develop novel molecular hybrid conjugates integrating isatin, rhodanine, and phthalimide pharmacophores to create effective analgesic and anti-inflammatory agents with improved safety profiles over existing treatments.

Materials & methods: A series of hybrid conjugates (4a - l) were synthesized and evaluated through in vitro and in vivo biological assays. The most promising compound, 4c, underwent extensive pharmacological and toxicological evaluations. Molecular docking, molecular dynamics simulations, and 2D-QSAR studies were performed to elucidate the mechanism of action and validate the experimental findings.

Results: Compound 4c exhibited potent analgesic and anti-inflammatory activity, effectively inhibiting COX-2 and pro-inflammatory cytokines (IL-6 and TNF-α). Its superior selectivity index (SI) was 1.11 compared to 0.67 for indomethacin. It demonstrated an ulcer index of 2.9 versus 10.23 for indomethacin, indicating reduced gastrointestinal toxicity. Molecular docking simulations revealed a strong binding affinity with COX-2 (-9.832 kcal/mol), and molecular dynamics confirmed the stability of the COX-2 complex.

Conclusions: Compound 4c emerged as a promising lead candidate for developing safer and more effective anti-inflammatory and analgesic agents. Its robust efficacy, safety profile, and computational validation highlight its potential for further optimization in therapeutic applications.