Quinolones have recently gained significant interest in oncology due to their structural versatility and broad pharmacological potential. Their modifiable scaffold makes them attractive candidates for anticancer drug development, enabling optimization of potency, selectivity, and pharmacokinetic properties. This review highlights recent advances in the synthesis of 2-quinolone and 4-quinolone derivatives, with an emphasis on emerging strategies such as metal-catalyzed reactions, photochemical approaches, base-mediated transformations, and metal-free methodologies. We summarize contemporary structure-activity relationship (SAR) studies that elucidate features governing anticancer activity in quinolone-based compounds. Additionally, we discuss mechanistic evidence demonstrating that quinolones exert antitumor effects through diverse molecular pathways, including topoisomerase inhibition, apoptosis induction, cell-cycle arrest, G-quadruplex stabilization, HDAC inhibition, modulation of miRNA processing, and regulation of key oncogenic signaling networks such as EGFR/PI3K/mTOR and S1P. The current landscape of quinolone-derived anticancer agents in preclinical and clinical development is also reviewed. Overall, this article provides a comprehensive and translational perspective on the synthetic advances, SAR insights, and mechanistic foundations supporting the development of 2- and 4-quinolone scaffolds as promising anticancer therapeutics.

Substituted Olefin-based compounds are attractive targets in the design of novel chemical structures for the discovery of new drugs. In the current study, we have synthesized a series of new tri-substituted olefin derivatives (4a–4p) and their chemical structures were confirmed by spectroscopic techniques. The series of molecules were evaluated for anti-cancer potential against four human cancer cell lines such as MDA-MB-232, HepG2, MCF-7 and HEK293. Among the evaluated compounds, ten compounds 4a, 4c, 4d, 4f, 4g, 4h, 4k, 4l, 4m and 4p displayed more potent anticancer activity. Along with anti-cancer we evaluated antimalarial activity of all compounds toward plasmodial strain PF3D7 via SYBR Green I assay approach and screened their Anti tuberculosis interest toward Mycobacterium tuberculosis. Graphical Abstract

Pharmacophore hybridization is a well-established strategy for developing novel anticancer agents with improved biological profiles. In this study, a new series of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide derivatives has been rationally designed by hybridizing key structural features of sorafenib with cinnamide pharmacophores and subsequently synthesized. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines, including A549 (lung), DU-145 (prostate), SKOV3 (ovarian), and HepG2 (liver), along with non-cancerous Hek293T cells. In comparison with the standard drug sorafenib, most of the (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamides demonstrated significant antiproliferative activity, with specificity toward the HepG2 (liver cancer) cell line, and no effect on the noncancerous cells (Hek293T). Among them, compound 5f, the derivative containing a trifluoromethyl-substituted cinnamoyl moiety was identified as the lead candidate, exhibiting an IC₅₀ of 5.3 µM towards HepG2 (liver) cancer cells, comparable to the reference drug sorafenib. Enzyme inhibition studies showed that compound 5f inhibited both b-Raf and VEGFR-2 with IC₅₀ values of 1.45 and 0.37 µM, respectively. Furthermore, compound 5f suppressed angiogenesis in vitro and in vivo, as evidenced by the tube formation assay using HUVECs and in transgenic zebrafish Tg(fli1a:EGFP) models, respectively. Mechanistic studies indicated that compound 5f induced apoptosis in HepG2 cells through mitochondrial membrane depolarization and increased ROS generation. Molecular docking studies supported experimental findings and showed that 5f can interact with catalytically active residues via hydrogen-bonding interactions. Overall, these results highlight the potential of compound 5f as a promising dual target therapeutic lead with dual direct anticancer and antiangiogenic properties.