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This study outlines the synthesis of pyrazine sulfonamides (3 a–3 i) along with halo‐phenyl derivatives (4 a–4 j and 5 a–5 e). The antiproliferative effects were tested against MCF‐7 breast cancer, and colon carcinoma HT‐29, HCT‐116 WT, and HCT‐116 p53 knock‐out mutant cell lines. Compounds 3 b and 3 c were notably active against HCT‐116 WT cells, while 3 e and 3 h were moderately effective against MCF‐7 cells. Among the halo‐phenyl sulfonamides, 4e and 4j were active against MCF‐7 cells, and 5 b was active against HCT‐116 WT cells. The most promising compounds were evaluated against non‐tumorigenic cells, demonstrating cancer selectivity. Compounds 3 b, 3 c, 3 e, 3 h, and 5 b showed dose‐dependent inhibition of colony formation. Compound 3 f exhibited free radical scavenging activity comparable to ascorbic acid. Molecular docking revealed strong binding to thymidylate synthase (3 b, 5 b), Akt‐3 protein kinase (3 e, 3 h, 4 e, 4 j), and tyrosinase (3 f, 3 h). The compounds also exhibited antiparasitic activity against Toxoplasma gondii and Leishmania major, with modifications enhancing selectivity for T. gondii. Substitutions in compounds 4 b and 4 d increased activity against T. gondii while reducing toxicity. Notably, compound 4 f emerged as a T. gondii‐selective lead drug. These findings suggest sulfonamides may help treat complex diseases like cancer and infections. [ABSTRACT FROM AUTHOR]

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4‐oxadiazole derivatives (compounds H4‐A‐F) of 6‐methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier‐transform infrared, proton nuclear magnetic resonance, and carbon‐13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer‐aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription‐polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4‐A, H4‐B, H4‐C, and H4‐E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4‐A, H4‐C, and H4‐F are nontoxic. Compound H4‐A showed the best‐fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4‐C was the most cytotoxic. Compound H4‐C caused cytotoxicity in HCT‐116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4‐D, H4‐C, and H4‐B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research. [ABSTRACT FROM AUTHOR]

Current chemotherapeutic agents have several limitations, including lack of selectivity, the development of undesirable side effects, and chemoresistance. As a result, there is an unmet need for the development of novel small molecules with minimal side effects and the ability to specifically target tumor cells. A new series of 3‐phenoxybenzoic acid derivatives, including 1,3,4‐oxadiazole derivatives (4a–d) and benzamides derivatives (5a–e) were synthesized; their chemical structures were confirmed by Fourier‐transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectra; and various physicochemical properties were determined. The antiproliferative activities of the new derivatives were evaluated by means of the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Three compounds (4b, 4c, and 4d) exhibited cytotoxicity against two of the three cell lines tested, five compounds (3, 4a, 5a, 5b, and 5e) were toxic to one cell line, while two compounds (5c and 5d) were not cytotoxic to any of the three cell lines tested in the current study. Based on docking scores, MTT assay findings, and vascular endothelial growth factor receptor 2 (VEGFR‐2) kinase activity data, Compound 4d was selected for further biological investigation. Flow cytometry was used to determine the mode of cell death (apoptosis vs. necrosis) and the effect on cell cycle progression. Compound 4d arrested HepG2 hepatocellular carcinoma cells in the G2/M phase and activated both the intrinsic and extrinsic apoptosis pathways. In conclusion, Compound 4d has shown promising results for future research as a potent VEGFR‐2 tyrosine kinase inhibitor. [ABSTRACT FROM AUTHOR]

Summary: Because of a reduced sensitivity of BRAF-mutant colorectal cancers to BRAF inhibitor treatment when compared with BRAF-mutant melanoma, it is essential to develop efficient drugs to cope with this disease. The new 2-(4-bromophenyl)-3-arylacrylonitrile compound Briva was prepared in one step from commercially available starting compounds. Briva and two known thiophene analogs (Thio-Iva and Thio-Dam) were tested for their cytotoxic activity against various tumor cell lines including colorectal and breast cancer cells. The antitumor activities of the test compounds were assessed in vitro via the MTT assay, DAPI staining of nuclei, RT-PCR and immunoblotting, wound healing, clonogenic assay, collagen I adhesion assay, and kinase inhibition assays. A selective activity of Briva was observed against BRAFV600E-mutant HT-29 and COLO-201 colorectal carcinoma (CRC) cells. Briva caused inhibition of HT-29 clonogenic tumor growth and was found to induce cytotoxicity by activating the intrinsic apoptosis pathway. In addition, Briva reduced HT-29 cell adhesion and migration. Kinase inhibition experiments revealed that Briva inhibits VEGFR2. Thus, Briva can be considered as a promising antitumor compound against BRAFV600E-mutant colon carcinoma by targeting VEGFR2 tyrosine kinase and consequently reducing cell adhesion and metastasis formation. [ABSTRACT FROM AUTHOR]