Synthesis and studies of biologic activity of new phenylurenyl chalcone derivatives

Yıldırım Akdeniz, G. Synthesis And Studies of Biologic Activity Of New Phenylurenyl Chalcone Derivatives. Yeditepe University Institute of Health Science, PhD Thesis on Pharmaceutical Chemistry Programme, İstanbul, 2020. The main purposes of this study were synthesis, characterization, biological activities, and molecular docking of novel compounds bearing {4-[(2E)-3-phenylprop-2-enoyl]phenyl}urea and {3-[(2E)-3-phenylprop-2-enoyl]phenyl}urea structures. In this study, novel compounds {4-[(2E)-3-phenylprop-2-enoyl]phenyl}urea and {3-[(2E)-3-phenylprop-2-enoyl]phenyl}urea derivatives were synthesized in two steps. Firstly; urenyl acetophenone derivatives (Compounds I-VI) were prepared by mixing of 4- or 3-aminoacetophenone and phenylisocyanate, benzylisocyanate or phenethylisocyanate in dry acetone under nitrogen atmosphere at room temperature. In the second step, urenyl acetophenone derivatives were reacted with related aldehydes at room temperature in the presence of excess sodium hyroxide in dry methanol to yield thirty two novel derivatives of phenylurenyl chalcone (Compounds 1-35). Structure identification of the compounds was done by spectral methods such as UV, IR, 1H NMR, 13C NMR, MS (ESI) and elementary analysis methods. Antimicrobial activities of the final compounds (Compounds 1-35) were screened against microorganisms of Staphylococcus aureus (ATCC 6538), Pseudomonas aeruginosa (ATCC 9027), Escherichia coli (ATCC 8739) and Candida albicans (ATCC 10231) by using the disc diffusion method. Compounds 3, 4, 11, 14, 22, 29 and 33 showed anti-bacterial activity against S. aureus, P. aeruginosa and E. coli while compounds 3, 4, 11, 14, 18, 22, 29, 33 and 34 had anti-fungal activity against C. albicans with inhibition zone of 14 mm. MIC values were calculated. The final compounds evaluated their cytotoxic effects on A-549 (human lung cancer cell line), Hep-3B (human liver cancer cell line), HT-29 (human colon cancer cell line), MCF-7 (human breast cancer cell line), PC-3 (androgen independent human prostate cancer cell line), K-562 (human leukemia cell line) and NIH-3T3 (mouse embryonic fibroblast normal cell line) cell lines by using the proliferation assay (MTT method). Only compounds 2, 26, 29, and 34 showed moderate cytotoxic activity on these cell lines. Another group of compounds were screened for cytotoxicity on Huh-7 (hepatocellular cancer) cell line with the Sulforhodamine B (SRB) method by another research group. Compounds 14 (IC50: 6.42 µM), 16 (IC50: 5.64 µM), 19 (IC50: 6.95 µM) and 34 (IC50: 6.87 µM) showed cytotoxic activity close to Sorafenib (IC50: 4.29 µM) (as reference). Within the scope of docking studies, the values of molecular weight (MA), human oral absorption percentage, polar surface area (PSA) and logarithm of octanol/ water coefficient ratio (QPlogP0/ W) of each synthesized substance regarding absorption, distribution, metabolism and elimination properties (ADME) were calculated using the QikProp module of the Schrödinger program. The best result for the Compound 34 with low MIC (minimal inhibition concentration) was obtained on CDK-2 receptor with the Glid XP method.