Novel pyridine‐derived compounds (5–19) were designed and synthesized, and their anticancer activities were evaluated against HepG2 and MCF‐7 cells, targeting the VEGFR‐2 enzyme. Compounds 10, 9, 8, and 15 were found to be the most potent derivatives against the two cancer cell lines, HepG2 and MCF‐7, respectively, with IC50 = 4.25 and 6.08 µM, 4.68 and 11.06 µM, 4.34 and 10.29 µM, and 6.37 and 12.83 µM. Compound 10 displayed higher activity against HepG2 cells than sorafenib (IC50 = 9.18 and 5.47 µM, respectively) and doxorubicin (IC50 = 7.94 and 8.07 µM, respectively). It also showed higher activity than doxorubicin against MCF‐7 cells, but lower activity than sorafenib. Compounds 9, 8, and 15 displayed higher activities than sorafenib and doxorubicin against HepG2 cells but exhibited lower activities against MCF‐7 cells. Compound 10 potently inhibited VEGFR‐2 at an IC50 value of 0.12 µM, which is nearly equipotent to sorafenib (IC50 = 0.10 µM). Compounds 8 and 9 exhibited very good activity with the same IC50 value of 0.13 µM. The six most potent derivatives, 6, 9, 8, 10, 15, and 18, were tested for their cytotoxicity against normal Vero cells. Compounds 6, 8, 9, 10, 15, and 18 are, respectively, 1.13, 3.74, 4.18, 3.64, 2.81, and 2.00 times more toxic to HepG2 and 2.06, 1.58, 1.76, 2.54, 1.40, and 2.69 times more toxic to MCF‐7 breast cancer cells than in normal Vero cells.

Novel heterocyclic derivatives (4–22) were designed, synthesized, and evaluated against hepatocellular carcinoma type (HepG2) and breast cancer (MCF‐7) cells, targeting the VEGFR‐2 enzyme. Compounds 18, 10, 13, 11, and 14 were found to be the most potent derivatives against both the HepG2 and MCF‐7 cancer cell lines, with GI50 = 2.11, 2.54 µM, 3.16, 3.64 µM, 3.24, 6.99 µM, 7.41, 6.49 µM and 8.08, 10.46 µM, respectively. Compounds 18 and 10 showed higher activities against both HepG2 and MCF‐7 cells than sorafenib (GI50 = 9.18, 5.47 µM, respectively) and doxorubicin (GI50 = 7.94, 8.07 µM, respectively). Compounds 13, 11, and 14 showed higher activities than sorafenib against HepG2 cancer cells, but lower activities against MCF‐7 cells. Compounds 18, 13, and 10 were more potent than sorafenib, inhibiting vascular endothelial growth factor receptor‐2 (VEGFR‐2) at GI50 values of 0.05, 0.06, and 0.08 µM, respectively. Compound 11 inhibited VEGFR‐2 at an IC50 value of 0.10 µM, which is equipotent to sorafenib. Compound 14 inhibited VEGFR‐2 at an IC50 value of 0.11 µM, which is nearly equipotent to sorafenib. The tested compounds have more selectivity against cancer cell lines. Compounds 18, 10, 13, 11, and 14 are, respectively, 16.76, 9.24, 6.06, 2.78, and 2.85 times more toxic in HePpG2 cancer cells than in VERO normal cells. Also, compounds 18, 10, 13, 11, and 14 are, respectively, 14.07, 8.02, 2.81, 3.18, and 2.20 times more toxic in MCF‐7 than in VERO normal cells. The most active compounds, 10, 13, and 18, showed a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile.

Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. Heterocyclic compounds present themselves as a fundamental division of organic chemistry. Most clinically effective antitumor agents are inhibitors of DNA, RNA or protein synthesis, enzyme inhibition and/or interfere with the metabolism of other cell components, frequently lacking or displaying poor selective antitumor activity. The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties have poised them as true cornerstones of medicinal chemistry. The S-heterocyclic core (Thiophene) has been reported to possess significant importance in various fields from medicinal chemistry. Many diverse biologically active products were prepared, several of which exhibited antimicrobial, analgesic, anti-inflammatory, antioxidant, antitumor, local anesthetic, anticoagulant and antithrombotic activities. Many N-heterocyclic compounds that are broadly distributed in Nature, possess physiological and pharmacological properties and are constituents of many biologically important molecules, including many vitamins, nucleic acids, pharmaceuticals, antibiotics, dyes and agrochemicals, amongst many others. The base pairs of DNA and RNA (Guanine, cytosine, adenine, and thymine) are also made up of N-heterocyclic compounds, namely purines, pyrimidines, etc. These nitrogen-containing heterocyclic molecules with distinct characteristics and applications have gained prominence in the rapidly expanding fields of organic and medicinal chemistry and the pharmaceutical industry. Finally, many of these compounds have higher activity against cancer cells using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)assay.

No abstract