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This study modified the solvent-exposed region of sunitinib by replacing its diethylaminoethyl tail with linear and heterocyclic amines, guided by lipophilicity, steric, and electronic considerations to enhance the anticancer activity and selectivity. Sunitinib and its 20 derivatives, including 14 new compounds (4a, 4c, 4d, 4g-4i, 5a, 5b, 7a-7e, and 8) and 6 known compounds (4b, 4e-4f, 5c-5d, and 6), were successfully synthesized. The cytotoxic effects of sunitinib and its derivatives were evaluated against three human cancer cell lines (HeLa, SH-SY5Y, and HepG2) and one normal cell line (L929) using the MTT assay. Sunitinib exhibited the strongest cytotoxicity toward SH-SY5Y neuroblastoma cells, with an IC₅₀ of 3.88 µM. Among the derivatives, compound 5b showed the highest potency with an IC₅₀ of 4.28 µM against SH-SY5Y. Compound 6 displayed the highest selectivity index (SI ≥ 5) for HeLa, indicating good selectivity toward cancer over normal cells. Overall, these results suggest that targeted modification of the solvent-exposed region in sunitinib can improve anticancer activity without toxicity against normal cell lines, with compound 5b emerging as a promising lead for further development, particularly against neuroblastoma. The solvent-exposed region is strategic for drug development, allowing modifications that improve affinity, selectivity, solubility, and pharmacokinetics without disrupting ligand-protein interactions.

A novel series of benzimidazole-based derivatives (5a-g), (6a-b), and (7a-b) were designed, synthesized, and evaluated for their potential as dual inhibitors of EGFR and HER-2. The synthesized compounds were subjected to in vitro screening against a panel of selected human cancer cell lines. Additionally, their cytotoxicity was assessed using normal human mammary epithelial cells (MCF-10A) to evaluate their safety profile. Among the tested derivatives, compounds 5b, 5f, and 6a demonstrated the most pronounced antiproliferative activity, exhibiting IC₅₀ values of 6, 8, and 5 µM, respectively. These values reflect a potency at least fourfold greater than that of the reference drug Doxorubicin (IC₅₀ = 33 µM). EGFR and HER-2 enzyme inhibition assays were conducted to explore the potential molecular targets responsible for the observed anticancer effects. Notably, compound 6a (R₁ = phenyl, thiosemicarbazide) exhibited superior efficacy against the MCF-7 breast cancer cell line, with an IC₅₀ of 5 µM, approximately six times more potent than Doxorubicin. Conversely, compound 7b, with an IC₅₀ value of 85 µM against MCF-7 cells, was the least active, underscoring the critical role of the phenyl moiety in antiproliferative activity. Furthermore, a molecular docking study was conducted to investigate the binding interactions of 6a within the active sites of EGFR and HER-2, providing insight into its potential mechanism of action.

Cancer remains a major global health challenge, responsible for millions of deaths each year. The limitations of current therapies, including adverse effects and drug resistance, have intensified the search for safer, more effective alternatives, particularly from natural sources. Alantolactone, a sesquiterpene lactone extracted from Inula helenium and related medicinal plants, has emerged as a promising anticancer candidate due to its diverse pharmacological actions. Although notable anticancer properties have been reported, its full therapeutic potential, mechanisms of action, and translational relevance remain insufficiently explored and scattered across the literature. This review provides a comprehensive synthesis of current evidence on alantolactone's anticancer effects. It examines its sources, phytochemical features, structure-activity relationships, bioavailability challenges, mechanistic pathways, and preclinical findings, alongside perspectives for future clinical application. Evidence shows that alantolactone modulates multiple molecular targets and signaling cascades, including NF-κB, STAT3, MAPK, and apoptotic regulators. It demonstrates strong cytotoxic activity across diverse cancer cell lines and tumor-bearing animal models. However, barriers such as low systemic bioavailability, limited pharmacokinetic profiling, and the absence of human clinical data impede its therapeutic development. Alantolactone nonetheless holds significant promise as a multi-targeted anticancer compound with encouraging preclinical outcomes. Further research is required to address pharmacological limitations and establish safety and efficacy in clinical contexts. This review highlights alantolactone's potential contribution to future cancer therapy and emphasizes the need for interdisciplinary research to support its clinical translation and formulation advancement.

Cancer prevails a substantial health threat, with breast and colon cancers being the second and third most recurrent worldwide. In recent decades, quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives have procured attention as propitious anticancer agents. This study acquaint a series of such compounds synthesized and characterized using spectroscopic (1H NMR, 13C NMR, IR, MS) and computational (DFT) methods. Their tubulin polymerization inhibitory and antiproliferative activities were assessed against cancer cell lines MCF-7, MDA-MB-231, and HCT-116, accompanying cytotoxicity screening against normal HEK-293 cells, divulging selective anticancer potential. SAR study accentuated the role of methoxy-substituted phenyl and cycloheptane rings in escalating activity. Peculiarly, compound 4g (IC₅₀ = 3.02 ± 0.63 μM against cell line MCF-7) exhibited profound tubulin inhibition and was additionally substantiated via molecular docking and dynamics simulations, ratifying its drug-like behavior.

Benz/imidazole-2-thione/selone-based triazoles, particularly their thione and selone analogs, are gaining attention for anticancer drug development due to their structural diversity and biological activity. However, their potential as targeted inhibitors of cancer-related proteins remains underexplored. This study reports the design, synthesis, and evaluation of novel benz/imidazole-2-thione/selone-based triazoles, focusing on cyclin-dependent kinase 1 (CDK1), a key regulator of cancer cell proliferation. The compounds were synthesized via a multistep approach involving imidazolium salt intermediates, followed by sulfur or selenium incorporation. Structural confirmation was achieved using FT-IR, NMR, and mass spectrometry. Molecular docking against CDK1, TERT, and VEGFR2 revealed strong binding affinities (-9.7 to -7.3 kcal/mol), with CDK1 selected for further in vitro study using MCF-7 breast cancer cells. Molecular dynamics (MD) simulations confirmed stable CDK1 binding for Compounds 2, 4, and 9, although Compound 9 showed conformational instability after 60 ns. ADMET profiling indicated favorable drug-likeness and permeability but highlighted metabolic liabilities and hERG inhibition risks, particularly for Compounds 4 and 9. The target prediction and pathway enrichment analyses predict that benz/imidazole-2-thione/selone-based triazoles exert their pharmacological effects primarily through the regulation of GPCR signaling pathways, likely via direct interaction with key regulators such as RGS8 and RGS4. In vitro assays demonstrated dose-dependent cytotoxicity, with Compound 4 showing the highest potency (IC₅₀ = 106.12 ± 1.03 µg/mL), followed by 9 and 2. These findings suggest that benz/imidazole-2-thione/selone-based triazoles are promising CDK1 inhibitors and support their further optimization as targeted breast cancer therapies.

The COVID-19 pandemic underscored the urgent need for effective antiviral agents, particularly against coronaviruses, which pose a continuing threat of future outbreaks. Targeting the main protease (M^pro), a key enzyme in viral replication, represents a promising therapeutic strategy. This study investigates structural modifications to known M^pro inhibitors, focusing on substitutions at the P2 position to explore alterations in both inhibitory potency and metabolic stability. Computational modeling and biochemical assays revealed that incorporating large, hydrophobic, and π-rich groups, such as the 4-phenylproline, significantly enhances binding affinity. Additionally, we evaluated warheads that have not yet been explored in the context of SARS-CoV-2 M^pro inhibition. Among these, fluoro-vinylsulfone and nitrile groups demonstrated superior inhibitory activity. A fragment-merging strategy combining an optimized P2 substituent with the nitrile warhead yielded a hybrid molecule with binding affinity comparable to nirmatrelvir. However, other analogs incorporating individual warhead optimizations displayed similar potency. These findings generate valuable insights into the design of robust M^pro inhibitors and support their potential development as broad-spectrum antiviral agents.