Modification of marketed drugs is an important way to develop drugs because its safety and clinical applicability. Oxygen-nitrogen heterocycles are a class of important active substances discovered in the process of new drug development. Dolutegravir, an HIV drug with a nitrogen-oxygen heterocycle structure, has the potential ability to inhibit cell survival. In order to find and explore novel anti-tumor drugs, new dolutegravir derivatives bearing different 1,2,3-triazole moieties were prepared via click reactions. In vitro biological experiments performed in several lung cancer cell lines suggested that these novel compounds displayed potent anti-tumor ability. Especially, the compound 9e with a substituent of 2-methyl-3-nitrophenyl and the compound 9p with a substituent of 3-trifluoromethylphenyl were effective against PC-9 cell line with IC₅₀ values of 3.83 and 3.17 µM, respectively. Moreover, compounds 9e and 9p were effective against H460 and A549 cells. Further studies suggested that compounds 9e and 9p could induce cancer cell apoptosis in PC-9 and H460, inhibit cancer cell proliferation, change the cell cycle, and increase the level of reactive oxygen species (ROS) which further induce tumor cell apoptosis. In addition, compounds 9e and 9p increased LC3 protein expression which was the key regulator in autophagy signaling pathway in PC-9 cells. Compound 9e also showed low toxicity against normal cells, and could be regarded as an interesting lead compound for further structure optimization.

This study explores the anticancer potential of rigid planar compounds capable of intercalating into tumor cell DNA, thereby inducing DNA damage and subsequent cell death. A novel series of compounds (c1–c20) were synthesized using 2H-1,4-benzoxazin-3(4H)-one as the planar core structure, with 1,2,3-triazole groups introduced at the 7-position. Biological evaluation across multiple human tumor cell lines revealed that several c-series compounds exhibited notable inhibitory activity against Huh-7 liver cancer cells, with IC₅₀ values of 28.48 μM (c5), 32.60 μM (c14), 31.87 μM (c16), and 19.05 μM (c18). Mechanistic studies indicated that these compounds effectively induced DNA damage, as evidenced by the upregulation of γ-H2AX, and triggered apoptosis via increased caspase-7 expression. Moreover, enhanced LC3 expression and autophagosome formation suggested the activation of autophagy pathways. The observed biological activities are likely attributed to the rigid planar configuration of the molecules, which facilitates DNA intercalation. Collectively, these results highlight the potential of these synthesized compounds as promising lead candidates for the development of novel therapeutic agents against liver cancer. Importantly, acute toxicity studies in mice demonstrated that these compounds possess favorable safety profiles, further supporting their potential for future preclinical development.

A series of 2H-benzo[b][1,4] oxazin-3(4H)-one derivatives linked to 1,2,3-triazoles were designed, synthesized, and evaluated for their anticancer activity in several human cancer cell lines, including A549 (lung), Huh7 (liver), MCF-7 (breast), HCT-116 (colon), and SKOV3 (ovary). Cell viability assays revealed that these compounds exhibited the most potent activity against A549 cells. Among them, compounds 14b and 14c demonstrated the strongest inhibitory effects, with IC₅₀ values of 7.59 ± 0.31 μM and 18.52 ± 0.59 μM, respectively. Flow cytometry analysis further confirmed that compounds 14b and 14c induced significant apoptosis. Additional studies showed that these compounds elevated reactive oxygen species (ROS) levels, which may contribute to apoptosis. Moreover, compounds 14b and 14c notably increased the number of dead cells while reducing viable cell counts. Western blot analysis indicated that these compounds could induce DNA damage and autophagy, which may play a key role in their anticancer effects.

This study applied a target-based drug design approach focused on the IDO1 enzyme, which features a heme active site. By introducing a 1,2,3-triazole moiety capable of coordinating with the ferrous ion in heme, a series of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives were designed. Enzyme assays demonstrated that these compounds generally inhibited IDO1 activity, with Compound 14e showing the most potent effect, achieving an IC₅₀ value of 3.63 μM. Molecular docking studies indicated that the 1,2,3-triazole ring in Compound 14e is positioned directly above the heme, forming a coordination bond with the ferrous ion. Additionally, it engages in π-π interactions with Phe263, while the amide group of the 2H-benzo[b][1,4]oxazin-3(4H)-one scaffold forms hydrogen bonds with Lys238. In vivo experiments in mice showed that Compound 14e significantly reduced CFA-induced upregulation of Iba1 in the spinal dorsal horn and alleviated mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain. Moreover, treatment with Compound 14e led to a significant reduction in the levels of pro-inflammatory cytokines TNF-α and IL-1β in CFA-treated mice. Importantly, Compound 14e demonstrated a favorable safety profile, with no observed toxicity in major organs, highlighting its potential as a promising anti-inflammatory and analgesic agent targeting IDO1.