Xinxin Zhou,Yicheng Mei,Baowei Yang,Jing Wang,Huiling Tang,Xiaolong Zhang,Changchun Liu
Eight 4-(morpholinyl arylamino)quinazoline-6-carbamoyl carboxylic acid methyl esters and four 4-(morpholinyl arylamino)quinazoline-6-carbamoyl hydroxamic acid derivatives were designed and synthesized by integrating morpholine moieties into the 4-aminoquinazoline scaffold, with additional modifications at the 6-position of quinazoline ring. The antitumor potential of these twelve derivatives was evaluated against human lung cancer A549 cells and breast cancer MDA-MB-231 cells using the Cell Counting Kit-8 (CCK-8) proliferation assays. The bioassay results indicated that most of the derivatives exhibited moderate to potent in vitro antiproliferative activity against both cancer cells. Particularly, compound 7bb demonstrated superior potency against MDA-MB-231 cells and A549 cells, with half maximal inhibitory concentration (IC 50 ) values of 4.286 and 4.720 μM, respectively, compared to the reference drug afatinib (IC 50 = 7.640 and 5.173 μM, respectively). This study provides valuable insights for the development of novel antitumor agents based on the 4-aminoquinazoline scaffold.
For highly sensitive and selective detection of ClO − over other reactive oxygen species (ROS) and anions, a fluorescent probe MN-BODIPY by introducing a morpholine group into the 8-position of BODIPY which could be used for targeting lysosome and improving water solubility was designed and synthesized. As a result of the C=N isomerization mechanism at 2-position of BODIPY, the probe alone generated extremely weak fluorescence. However, in the presence of ClO − , the probe exhibited a dramatic enhancement of fluorescence intensity by a 29-fold increase at 530 nm accompanying with quantum yield changing from 0.03 to 0.25. Accordingly, the probe displayed fast response for ClO − within 60 s. The limit of detection (LOD) for ClO − was calculated as 16.5 nM from the titration experiments, which is lower than most previously reported ClO − -selective probes. Moreover, MN-BODIPY had been successfully employed for monitoring exogenous and endogenous hypochlorous in MCF-7 cells with satisfying results, perhaps it was feasible for detecting abnormal contents of hypochlorous in a biological system and accomplished the goal of maintaining normal human activities. At last, the fluorescence imaging showed that MN-BODIPY was capable of localizing lysosomes in living cells.
Compounds containing a 1,3,5-triazine skeleton exhibit broad-spectrum biological activity, particularly in the fields of antiviral, antibacterial, anticancer, and anti-inflammatory properties in medicine. In this study, a series of 1,3,5-triazine derivatives containing morpholine group were designed and synthesized. Their structures were identified by 1 H NMR, 13 C NMR, HRMS and X-ray single crystal diffraction, and their antiviral activity against pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) was evaluated. The results of cell-based assays revealed that some target compounds possessed excellent antiviral effect against PRV and VSV. Compounds 10ce (SI: 30.82 against PRV, 16.19 against VSV) and 10de (SI: 10.26 against PRV, 13.22 against VSV) exhibited excellent antiviral activity, with significantly higher selectivity indices compared to other derivatives. Further investigations revealed that both compounds effectively inhibited the viral progeny titers of both PRV and VSV. This antiviral activity was corroborated by Western blot and qRT-PCR analyses, which demonstrated significant downregulation of the corresponding viral proteins and their associated genes. Molecular docking studies demonstrated that compounds 10ce and 10de bound to the active site of PIKfyve with binding energies of -11.2 kcal/mol and -11.4 kcal/mol, respectively, forming hydrogen bonds and hydrophobic interactions. These findings suggest that their antiviral effects may be mediated through interactions with PIKfyve. Moreover, cytotoxicity assays showed that the CC50 values of compounds 10ce and 10de were 47.77 μM and 46.39 μM, respectively, indicating their relatively high safety profiles. These results suggest that 1,3,5-triazine-based compounds are highly promising candidate drugs worthy of further development.
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