A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3’-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one, achieving IC₅₀ = 1.2 ± 0.2 µM and 1.4 ± 0.2 µM against MCF-7 and Panc-1 cell lines, respectively. Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant pro-apoptotic activity is indicated by annexin V-FITC staining.

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, ¹³C NMR, ¹H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC₅₀ = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC₅₀ values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC₅₀ = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors.

Background/Objectives: The dual inhibition of the COX-2 and 5-LOX pathways, in addition to sEH inhibition, presents a superior approach to managing inflammation while mitigating the cardiovascular adverse effects typically associated with conventional NSAIDs. These multi-target agents are safer and more efficient as they inhibit the synthesis of pro-inflammatory leukotrienes while preserving cardioprotective epoxyeicosatrienoic acids. Methods: This study reports the development of multi-target inhibitors to mitigate inflammatory and cardiovascular conditions. We examined a series of tetrahydroindazole-sulfonamide hybrids (3a–g and 4a–e) against the enzymes COX-1/2, 5-LOX, and sEH. Results: Compound 3b outperformed celecoxib as a multi-target agent, inhibiting COX-2 (IC₅₀ = 0.08 µM, SI = 82), 5-LOX (IC₅₀ = 0.46 µM), and sEH (IC₅₀ = 21.95 nM) in many metrics. In cellular experiments, 3b showed strong cardioprotective and anti-inflammatory effects, significantly reducing TNF-α (65.58%), LDH (76.26%), and CK-MB (76.76%) levels compared to LPS-treated controls. Molecular docking validated these findings, indicating that 3b was comparable to celecoxib at the COX-2 site via a thorough six hydrogen-bond network and achieves considerable sEH affinity through specialized halogen bonding and aromatic stacking. These results indicate that 3b effectively provides dual anti-inflammatory and cardioprotective effects. Conclusions: Our findings suggest that targeting the COX/5-LOX/sEH pathways simultaneously offers a balanced multi-target profile for treating complex inflammatory diseases while minimizing cardiovascular risks.