Synthesis and Rational Design of New Appended 1,2,3-Triazole-uracil Ensembles as Promising Anti-Tumor Agents via In Silico VEGFR-2 Transferase Inhibition

Abstract

Angiogenesis inhibition is a key step towards the designing of new chemotherapeutic agents. In a view to preparing new molecular entities for cancer treatment, eighteen 1,2,3-triazole-uracil ensembles 5a–r were designed and synthesized via the click reaction. The ligands were well characterized using 1H-, 13C-NMR, elemental analysis and ESI-mass spectrometry. The in silico binding propinquities of the ligands were studied sequentially in the active region of VEGFR-2 using the Molegro virtual docker. All the compounds produced remarkable interactions and potentially inhibitory ligands against VEGFR-2 were obtained with high negative binding energies. Drug-likeness was assessed from the ADME properties. Cytotoxicity of the test compounds was measured against HeLa and HUH-7 tumor cells and NIH/3T3 normal cells by MTT assay. Compound 5h showed higher growth inhibition activity than the positive control, 5-fluorouracil (5-FU), against both HeLa and HUH-7 cells with IC50 values of 4.5 and 7.7 μM respectively. Interestingly, the compounds 5a–r did not show any cytotoxicity towards the normal cell lines. The results advance the position of substituted triazoles in the area of drug design with no ambiguity.

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents

“…In previous studies, hybrids of uracil with heterocycle groups were reported as potent compounds for cytotoxic activity. For example, compound A is a hybrid of uracil and oxadiazole with IC 50 = 0.88 μM against a studied cancer cell line [ 13 ], and compound B, bearing uracil and 1,2,3-triazole exhibited a promising cytotoxic with IC 50 = 4.5 and 7.7 μM against Hela and Huha cell lines respectively [ 31 ]. According to the stated items, 3-methyl–pyrimidine-2,4-dione was conjugated with various azole rings bearing benzyl or benzoyl substitution at the N-1 position of uracil with different electronic profiles (Fig.…”

As Antimicrobial Agents: Synthesis, Structural Characterization and Molecular Docking study of Barbituric Acid Derivatives from Phenobarbital

“…Virtual molecular docking studies were used to investigate the inhibitory potential of produced compounds [29]. Virtual screening was performed using Molegro Virtual Docker (MVD), which was installed on an Intel Core i7 9700k processor with 120 GB SSD, 1 TB hard drive, and an NVIDA GeForce GTX 1050 graphics card [30,31].…”

“…8a showed six hydrogen bond interactions along with six different types of interactions comprising VdW, hydrogen bond, pi-donor, pi-lone pair, and alkyl interactions with dihydropteroate synthetize. Antifolate showed total four hydrogen bond interactions [31].…”

“…Maximum iteration to 2000 and 50 maximum population size [29,30]. Discovery Studio Visualizer was used for generation of 3D and 2D protein-ligand interactions [31,45].…”

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research

“…Additionally, the report stating that 5-FU inhibits VEGF-mediated angiogenesis is noteworthy [ 47 ]. According to Reddy et al [ 48 ], 5-FU interacts with the VEGFR-2 active site through the formation of conventional hydrogen bonds by the –NH and carbonyl groups of the uracil moiety with Glu885 (2.37 Å) and Asp1046 (2.03 Å), respectively. Cisplatin, on the other hand, is particularly effective in treating various types of lung cancer [ 49 ].…”