Eman Omar Osman

Abstract New pyridazine and pyridazinone derivatives 3a–g, 4a–f, 6a, and 6b were designed and synthesized. Cell viability of all compounds was established based on the viability of lipopolysaccharide-induced RAW264.7 macrophage cells determined via the MTT assay. In vitro inhibition assays on human COX-1 and COX-2 enzymes were conducted to probe the newly synthesized compounds' anti-inflammatory activity. The half maximal inhibitory concentration values for the most active compounds, 3d, 3e, and 4e towards COX-2 were 0.425, 0.519, and 0.356 µM, respectively, in comparison with celecoxib. The newly synthesized compounds' ability to inhibit the production of certain proinflammatory cytokines, such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-6, and prostaglandin-E2, was also estimated in lipopolysaccharide-induced macrophages (RAW264.7 cells). Compounds 3d and 3e were identified as the most potent cytokine production inhibitors. The results of molecular modeling studies suggested that these compounds were characterized by a reasonable binding affinity toward the active site of COX-2, when compared to a reference ligand. These results might be taken into consideration in further investigations into new anti-inflammatory agents.

Abstract A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor-2 (VEGFR-2) with an IC50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR-2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51-fold increment in total apoptotic level in leukemia cell line HL-60(TB) and a 6.91-fold increase in the caspase-3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram-positive a70am-negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 μg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram-negative DNA gyrase with IC50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR-2 active site and compounds 3a–c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties.

This study synthesized novel ciprofloxacin analogs bearing the 2-amino-1,3,4-thiadiazole ring, including tryptophan and different sulfonamides, to act as antimicrobial agents. Then, the activities of the synthesized hybrids were screened against 18 tested bacterial isolates from 4 standard strains (Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 25,923, Acinetobacter baumannii ATCC 19,606, and Pseudomonas aeruginosa PAO1) and 14 clinical strains (2 Enterobacter cloacae and 12 Klebsiella pneumonia isolates). Investigations revealed that compound 2 showed better antimicrobial activities among the synthesized compounds than the standard drug, ciprofloxacin, demonstrated by its lower MIC and MBC values. We also notably observed that compared to ciprofloxacin, compound 2 maintained its activity for a longer time without inducing resistance in the tested bacterium. Hence, we conducted a time-to-kill assay and compared the results with its parent drug, followed by a molecular modeling simulation study through the docking of compound 2 into E. coli DNA gyrase enzyme active site to elucidate its binding modes to the receptor. Then, we compared these results with ciprofloxacin and calculated the physicochemical descriptors, ADME parameters, pharmacokinetic properties, and drug-like nature profile of compound 2 as the most potent were also calculated. Based on our findings, we conclude that with further modifications of compound 2, the design of a new and optimized fluoroquinolone generation should be possible.

Abstract Two series of quinazolinone derivatives were designed and synthesized as dihydrofolate reductase (DHFR) inhibitors. All compounds were evaluated for their antibacterial and antitumor activities. Antibacterial activity was evaluated against three strains of Gram-positive and Gram-negative bacteria. Compound 3d exhibited the highest inhibitory activity against Staphylococcus aureus DHFR (SaDHFR) with IC50 of 0.769 ± 0.04 μM compared to 0.255 ± 0.014 μM for trimethoprim. Compound 3e was also more potent than trimethoprim against Escherichia coli DHFR (EcDHFR) with IC50 of 0.158 ± 0.01 μM and 0.226 ± 0.014 μM, respectively. Compound 3e exhibited a promising antiproliferative effect against most of the tested cancer cells. It also showed potent activity against leukemia (CCRF-CEM, and RPMI-8226); lung NCI-H522, and CNS U251 with GI% of 65.2, 63.22, 73.28, and 97.22, respectively. The cytotoxic activity of compound 3e was almost half the activity of doxorubicin against CCRF-CEM cell line with IC50 of 1.569 ± 0.06 μM and 0.822 ± 0.03 µM, respectively. In addition, compound 3e inhibited human DHFR with IC50 value of 0.527 ± 0.028 µM in comparison to methotrexate (IC50 = 0.118 ± 0.006 µM). Compound 3e caused an arrest of the cell cycle mainly at the S phase and caused a rise in the overall apoptotic percentage from 2.03% to 48.51%. (23.89-fold). Treatment of CCRF-CEM cells with compound 3e produced a significant increase in the active caspase-3 level by 6.25-fold compared to untreated cells. Molecular modeling studies were performed to evaluate the binding pattern of the most active compounds in the bacterial and human DHFR.

The current work reported the first synthesis of 4H-pyran derivatives via one pot reaction of dimedone, malononitrile and aromatic aldehydes under electrochemical (EC) synthesis conditions in deep eutectic solvents (DES). The effects of different experimental factors like; solvent, electrodes, supporting electrolytes, temperature and reaction time were studied to optimize the reaction conditions in order to maximize the products yield. The reaction proceeded completely using different substituted aldehydes except for hydroxybenzaldehydes where oxidation seems to hinder the formation of the target reaction product. Combining EC and DES afforded the pyran derivatives in high yields within short reaction times and in highly pure forms. Moreover, the use of DES eliminated the need for supporting electrolyte. The DES have been recycled two times without a significant loss in the catalytic activity. The procedure was highly efficient, catalyst-free and eco-friendly as evident from the calculations of the green chemistry metrics.