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An efficient synthesis of a series of uracil analogous was performed to obtain new potential anticancer agents. The cytotoxic effect of the synthesized derivatives was assessed in vitro against three cancer cell lines, namely hepatic cancer (HepG-2), colon cancer (HCT-116), and breast cancer (MCF-7). Among the tested compounds, 5, 11 and 15 stood as potent uracil derivatives with pan cytotoxicity against the 3 cell lines out-performing the reference compound 5-FU. Furthermore, selected compounds underwent thymidylate synthase (TS) enzyme inhibition assay and demonstrated effective inhibition of the enzyme's catalytic activity. Thereafter, flow cytometric apoptosis and protein expression of pro- and anti-apoptotic markers Bax, BCL-2, PI3K, and STAT1 proteins assays were performed employing the most active compound on the respective most responsive cell line and compounds demonstrated effectiveness in inducing apoptosis in the treated cell lines. Finally, in silico studies encompassing molecular docking and molecular dynamics studies were also conducted to predict the interaction mechanisms and stability of the active compounds within the active site of their biological target TS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work is protected under patent application (EG/P/2024/1425)., (Copyright © 2024. Published by Elsevier Inc.)

Background : Alzheimer's disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective : This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods : Ten novel pyridazine-containing compounds were synthesized and characterized using IR, 1 H NMR, and 13 C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results : Compound 5 was the most potent inhibitor, with IC 50 values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of -10.21 kcal/mol to AChE and -13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5 , 8 , and 9 , with Compound 5 showing the best activity. Conclusions : Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer's disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors.

New thienyl- or chlorophenyl-substituted thiazolopyrimidine derivatives and their derived sugar hydrazones incorporating acyclic d-galactosyl or d-xylosyl sugar moieties in addition to their per-O-acetylated derivatives were synthesized. Heterocyclization of the formed sugar hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the cyclization process. The cytotoxic activity of the synthesized compounds was studied against human breast cancer MCF7 and MDA-MB-231 cell lines as well as human colorectal cancer HCT 116 and Caco-2 cell lines. High activities were revealed by compounds 1 , 8 , 10 , 11 , and 13 against Caco-2 and MCF7 cells in addition to moderate activities exhibited by other compounds against HCT116 or MDA-MB-231 cells.