Synthesis, biological activities, and molecular docking studies of triazolo[4,3-b]triazine derivatives as a novel class of α-glucosidase and α-amylase inhibitors.

In diabetes mellitus, amylase and glucosidase enzymes are the primary triggers. The main function of these enzymes is to break macromolecules into simple sugar units, which directly affect blood sugar levels by increasing blood permeability. To overcome this metabolic effect, there is a need for a potent and effective inhibitor capable of suppressing the enzymatic conversion of sugar macromolecules into their smaller units. Herein, we reported the discovery of a series of substituted triazolo[4,3-b][1,2,4]triazine derivatives as α-glucosidase and α-amylase inhibitors. All target compounds demonstrated significant inhibitory activities against α-glucosidase and α-amylase enzymes compared with acarbose as the positive control. The most potent compound 10k, 2-[(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)thio]-N-[4-(trifluoromethyl)phenyl]acetamide, demonstrated IC50 values of 31.87 and 24.64 nM against α-glucosidase and α-amylase enzymes, respectively. To study their mechanism of action, kinetic studies were also done, which determined the mode of inhibition of both enzymes. Molecular docking was used to confirm the binding interactions of the most active compounds.

Synthesis of novel 2-acetamide-5-phenylthio-1,3,4-thiadiazole-containing phenyl urea derivatives as potential VEGFR-2 inhibitors.

A novel series of 2-acetamide-5-phenylthio-1,3,4-thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT-29, A431, and PC3, as well as normal HDF cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4-chloro-containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl-2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR-2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three-dimensional cell culture method using the hanging drop technique.

Quinazolin-4(3H)-one based agents bearing thiadiazole-urea: Synthesis and evaluation of anti-proliferative and antiangiogenic activity.

A series of quinazolin-4(3H)-one based agents containing thiadiazole-urea were designed, synthesized, and biologically evaluated. The proliferation rate of PC3 cells was moderately reduced by compound 9f (IC50 = 17.7 µM)which was comparable with sorafenib (IC50 = 17.3 µM). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC50 = 6.1 µM). To test the potential of compounds in inducing apoptosis, Annexin V-FITC/propidium iodide double staining assay was used. After the treatment of HUVEC cells with 9f, they underwent apoptotic effects. A substantial effort was dedicated to gathering comprehensive data across CAM assay. These data showed that 9f moderately inhibits the growth of corresponding blood vessels. Finally, the outcomes of Western blotting proposed a mechanism of action, by which the phosphorylation of VEGFR-2 is inhibited by compounds 9f and 9y.

Synthesis and anti-cancer activity evaluation of new dimethoxylated chalcone and flavanone analogs.

A novel series of chalcones and flavanones discriminated by the presence of a 3,4-dimethoxyphenyl moiety in their structures were synthesized as anti-cancer agents. The cytotoxicity evaluation of the analogs against the MCF-7, MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cell lines demonstrated that the introduction of a halogen on the 3,4-dimethoxyphenyl part of both series and the attachment of a pyrrolidinylethoxy group on the C-7 position of the flavanone derivatives increased their activity. Indeed, 3-halogenated chalcones (1c and 1d) were more potent than the standard drug etoposide against all tested cell lines. Fluorescence microscopy and flow cytometry analyses confirmed that the anti-cancer effect of the most potent compounds 1c and 1d occurs via apoptosis induction.