Design and Synthesis of Quinoxaline Hybrids as Modulators of HIF-1a, VEGF, and p21 for Halting Colorectal Cancer.

A library of 16 3-benzyl-N 1-substituted quinoxalin-2-ones was synthesized as N 1-substituted quinoxalines and quinoxaline-triazole hybrids via click reaction. These compounds were tested for their anticancer activity via MTT assay on HCT-116 and normal colonocyte cell lines to assess their cytotoxic potentials and safety profiles. Overall, compounds 6, 9, 14, and 20 were found to be promising anticolorectal cancer agents; they exhibited remarkable cytotoxicity (IC50 0.05-0.07 µM) against HCT-116 cells within their safe doses (EC100) on normal colon cells. Their pronounced anticancer activities were observed as severe morphological alterations and shrinkage of the treated cancer cells. Besides, qRT-PCR analysis was conducted showing the potential of the promising hits to downregulate HIF-1a, VEGF, and BCL-2 as well as their ability to enhance the expression of proapoptotic genes p21, p53, and BAX in HCT-116 cells. In silico prediction revealed that most of our compounds agree with Lipinski and Veber parameters of rules, in addition to remarkable medicinal chemistry and drug-likeness parameters with no CNS side effects. Interestingly, docking studies of the compounds in the VEGFR-2' active site showed significant affinity toward the essential amino acids, which supported the biological results.

Exploration of Nitroaromatic Antibiotics via Sanger's Reagent: Synthesis, In Silico, and Antimicrobial Evaluation.

Facile synthesis of molecular hybrids containing a 2,4-dinitrophenyl moiety was achieved via nucleophilic aromatic substitution of the fluoride anion of Sanger's reagent (2,4-dinitrofluorobenzene) with various N, S, and O nucleophiles, considered as bioactive moieties. Antimicrobial evaluation of the new hybrids was carried out using amoxicillin and nystatin as antibacterial and antifungal reference standards, respectively. MIC test results identified the compounds 3, 4, and 7 as the most active hybrids against standard strains and multidrug-resistant strains (MDR) of Staphylococcus aureus, Escherichia coli, and Pseudomonas aurginosa. Most of the hybrids displayed two times the antibacterial activity of AMOX against MDR Pseudomonas aeruginosa, E. coli, and a standard strain of P. aeruginosa (ATCC 29853), while demonstrating a weak antifungal profile against Candida albicans. Selectivity profiles of the promising compounds 3, 4, 6, 7, 8, and 11 on WI-38 human cells were characterized, which indicated that compound 3 is the safest one (CC50 343.72 µM). The preferential anti-Gram-negative activity of our compounds led us to do docking studies on DNA gyrase B. Docking revealed that the potential antimicrobial compounds fit well into the active site of DNA gyrase B. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) predictions revealed that most of the new compounds have high gastrointestinal absorption and a good oral bioavailability with no BBB permeability.