Design, Synthesis, Biological Evaluation and Molecular Docking Studies of a New Series of Maleimide Derivatives.

Eyilcim Ö ，Günay F ，Ng YY ，Ulucan Açan Ö ，Turgut Z ，Günkara ÖT ... -  《ChemistryOpen》

Novel 5-Fluorouracil analogues versus perfluorophenyl ureas as potent anti-breast cancer agents: Design, robust synthesis, in vitro, molecular docking, pharmacokinetics ADMET analysis and dynamic simulations.

To investigate the therapeutic potential of 5-Fluorouracil-based analogues, a straightforward synthetic technique was employed to synthesize a novel series of 5-arylurea uracil derivatives (AUFU01-03) and aryl-urea derivatives bearing perfluorophenyl (AUPF01-03). Reliable tools such as infrared (IR), Nuclear Magnetic Resonance (NMR) spectra, and elemental analyses were utilized to confirm the chemical structures and purity of these compounds. In comparison to healthy noncancerous control skin fibroblast cells (BJ-1), we examined the antiproliferative efficacy of compounds (AUFU01-03) and (AUPF01-03) against specific human malignant cell lines of the breast (MCF-7), and colon (HCT-116). Based on the MTT experiment results, compounds AUFU03 and AUPF01-03 possessed highly cytotoxic effects. Among these, cytotoxicity was demonstrated by compounds AUPF01-03 with IC50 values (AUPF01, IC50 = 167 ± 0.57 µM, AUPF02, IC50 = 23.4 ± 0.68 µM and AUPF03, IC50 = 28.8 ± 1.13 µM, respectively, on MCF-7), relative to 5-Fluorouracil as reference drug (IC50 = 160.7 ± 0.22 µM). Compound AUPF01 showed safety on BJ-1 cells up to a concentration of 100 µM (% cytotoxicity = 3.9 ± 0.42 %), so AUPF01 was selected for further studies. At the gene, the expression levels of BCL-2 gene were decreased significantly in MCF-7 + 5-FU and reached the lowest level in MCF-7 + AUPF01. In contrast, the expression levels of pro-apoptotic genes (p53 and BAX) were increased in MCF-7 + 5-FU, and reached a significantly higher level in MCF-7 + AUPF01. Apoptosis/necrosis assays demonstrated that AUPF01 induced S and G2/M phase cell cycle arrest in MCF-7 cells. Moreover, the efficacy of these compounds against anti-cancer protein receptors was assessed using molecular docking. The results indicated that compound AUPF01 exhibited high binding energies, effectively interacting with the active sites of crucial proteins such as EGFR, CDK2, ERalfa, BAX1, BCL2, and P53. These interactions involved a diverse range of chemical bonding types, suggesting the potential of these substances to inhibit enzyme activities. Moreover, computational ADMET analyses of these compounds demonstrated compliance with Lipinski's criteria, indicating favorable physicochemical properties. Additionally, molecular dynamics (MD) simulations revealed stable complexes of AUPF01 with EGFR, CDK2, ERalfa, BAX1, BCL2, and P53, as evidenced by (RMSD) values, RMSF values, and (SASA) values for the respective complexes.

Sroor FM ，El-Sayed AF ，Mahmoud K 《-》

New 1,3,4‒oxadiazole Quinazolines as Potential Anticancer Agents: Design, Synthesis, Biological Evaluation, and In silico Studies.

A novel series of 1,3,4‒oxadiazole connected to derivatives of quinazolinone (7a-e and 8a-f) was synthesized in the current investigation, and its anticancer and Topoisomerase‒ II inhibitory activity was evaluated. These findings inspired the design, synthesis, and biological analysis of these 1,3,4‒oxadiazole-quinazolinone analogues as antiproliferative Topo‒II inhibitors. The novel compound structures were determined using mass spectrometry and spectral methods (IR, NMR: 1H & 13C). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colourimetric assay has been used to evaluate the anticancer efficacy of these drugs, and Autodock 4.2 provides a description of the docking results. For the more active members, additional biological tests, such as the Topo‒II inhibition experiment, were performed. These compounds' physicochemical and ADMET characteristics were examined in more detail. In the experiment for antiproliferative activity, compounds 7d, 7e, 8c, 8e, and 8f demonstrated encouraging cytotoxicity findings against HCT‒116 and HepG2 cancer cell lines, with IC50 values ranging from 3.85 to 19.43 μM. Compounds 7d, 7e, and 8e were the most potent inhibitors of Topo II with IC50 values of 15.18, 17.55, and 12.59 μM, respectively. Additionally, the docked compound 8c showed the strongest conventional hydrogen bonds among the residues Leu507(B), Asn508(B), Asn520(B), and Glu522(B) in the Human topoisomerase‒IIβ active site in the DNA complex (4G0U) when compared to the findings of docking experiments. New findings have discovered the fact that fused 1,3,4‒oxadiazole bearing quinazolinone contributed great significance in the field of medicinal chemistry due to their diverse biological properties. Finally, the in silico pharmacokinetic profile of all the synthesized derivatives was estimated using SwissADME, where some of the compounds followed Lipinski, Veber, Egan, and Muegge rules without deviation. The result of this activity advises that with a simple modification in structure, a potent anticancer agent can be generated with good efficacy.

Gujja V ，Sadineni K ，Koppula SK ，Basireddy A ，Venkanna B ，Gunda SK ... -  《-》

Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells.

Dhanalakshmi B ，Anil Kumar BM ，Muddenahalli Srinivasa S ，Vivek HK ，Sennappan M ，Rangappa S ，Srinivasa Murthy V ... -  《-》

Synthesis of S-alkylated oxadiazole bearing imidazo[2,1-b]thiazole derivatives targeting breast cancer: In vitro cytotoxic evaluation and in vivo radioactive tracing studies.

Mohammed ER ，Abdel Fattah Ezzat M ，Seif EM ，Essa BM ，Abdel-Aziz HA ，Sakr TM ，Ibrahim HS ... -  《-》