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Diabetes is a chronic metabolic disorder of the endocrine system characterized by persistent hyperglycemia appears due to the deficiency or ineffective use of insulin. The glucose level of diabetic patients increases after every meal and medically recommended drugs are used to control hyperglycemia. Alpha-glucosidase inhibitors are used as antidiabetic medicine to delay the hydrolysis of complex carbohydrates. Acarbose, miglitol, and voglibose are commercial drugs but patients suffer side effects of flatulence, bloating, diarrhea, and loss of hunger. To explore a new antidiabetic drug, a series of benzotriazinone carboxamides was synthesized and their alpha-glucosidase inhibition potentials were measured using in vitro experiments. The compounds 14k and 14l were found to be strong inhibitors compared to the standard drug acarbose with IC50 values of 27.13 ± 0.12 and 32.14 ± 0.11 μM, respectively. In silico study of 14k and 14l was carried out using molecular docking to identify the type of interactions developed between these compounds and enzyme sites. Both potent compounds 14k and 14l exhibited effective docking scores by making their interactions with selected amino acid residues. Chemical hardness and orbital energy gap values were investigated using DFT studies and results depicted affinity of 14k and 14l towards biological molecules. All computational findings were found to be in good agreement with in vitro results. [ABSTRACT FROM AUTHOR]

• Sequential olefin hydroboration/palladium-catalyzed alkyl suzuki coupling. • Easy access to ortho n -alkyl benzamides from anthranilic acid derivatives. • Readily available α-olefins as primary alkyl sources. • High primary alkyl selectivity. A denitrogenative alkylation of N -aryl benzotriazinones using readily available α-olefins as alkyl sources via a hydroboration/palladium-catalyzed alkyl Suzuki coupling sequence is reported to afford ortho n -alkyl benzamides in good to excellent yields. Scope and limitations of the sequential hydroboration/Suzuki coupling protocol have been explored, showing large steric effects of both benzotriazinone core and alkylboranes. Only primary alkyl group of trialkylboranes from anti -Markovnikov hydroboration of α-olefins could be effectively coupled, making the protocol highly selective for ortho n -alkyl benzamides. A highly selective hydroboration/palladium-catalyzed alkyl Suzuki coupling sequence is reported for efficient access to ortho n -alkyl secondary N -arylbenzamides from anthranilic acid derived 1,2,3-benzotriazinones under mild conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

Diabetes is a chronic metabolic disorder of the endocrine system characterized by persistent hyperglycemia appears due to the deficiency or ineffective use of insulin. The glucose level of diabetic patients increases after every meal and medically recommended drugs are used to control hyperglycemia. Alpha-glucosidase inhibitors are used as antidiabetic medicine to delay the hydrolysis of complex carbohydrates. Acarbose, miglitol, and voglibose are commercial drugs but patients suffer side effects of flatulence, bloating, diarrhea, and loss of hunger. To explore a new antidiabetic drug, a series of benzotriazinone carboxamides was synthesized and their alpha-glucosidase inhibition potentials were measured using in vitro experiments. The compounds 14k and 14l were found to be strong inhibitors compared to the standard drug acarbose with IC50 values of 27.13 ± 0.12 and 32.14 ± 0.11 μM, respectively. In silico study of 14k and 14l was carried out using molecular docking to identify the type of interactions developed between these compounds and enzyme sites. Both potent compounds 14k and 14l exhibited effective docking scores by making their interactions with selected amino acid residues. Chemical hardness and orbital energy gap values were investigated using DFT studies and results depicted affinity of 14k and 14l towards biological molecules. All computational findings were found to be in good agreement with in vitro results.

An approach for the construction of benzotriazinone-triazole system is described. The synthesis is based on diazonium chemistry and subsequent intramolecular heteroatom-heteroatom bond formation. The introduction of triazole moiety occurred via click reaction catalyzed by nano-sized copper, supported on modified silica mesopore KIT-5 leading to the desired products in excellent yield. Also, in vitro acetylcholinesterase (AChE) inhibitory activities of the target compounds were screened by Ellman's method. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design and structure–activity relationship of novel GSPT1 degraders with benzotriazinone scaffold (TD-105) • 34f (TD-522) exhibit strong anti-proliferative effect in both KG-1 AML and TMD-8 DLBCL cell lines. • 34f effectively induce GSPT1 degradation with DC 50 of 0.269 nM in KG-1 cells. • 34f effectively suppress TMD-driven tumor growth in xenograft model. Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure–activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC 50 = 0.5 nM) and TMD-8 (EC 50 = 5.2 nM) cell lines. Compound 34f effectively induced GSPT1 degradation with a DC 50 of 0.269 nM and Dmax of >95 % at 10 nM concentration in KG-1 cells. An in vivo xenograft study showed that compound 34f effectively suppressed TMD8-driven tumor growth, suggesting a potential role in the development of novel GSPT1 degraders. [ABSTRACT FROM AUTHOR]

Several new 4(3 H)-1,2,3-benzotriazinone derivatives were synthesized and tested for their anti-inflammatory activity and ulcerogenic effect. A docking study on the COX-2 binding pocket has been carried out for the target compounds to rationalize the possible selectivity. Among the tested compounds, the benzotriazinones linked to either thiadiazole (8) or oxadiazole (9) evoked the highest anti-inflammatory activity as well as the best binding profiles into the COX-2 binding site. [ABSTRACT FROM AUTHOR]

The crystal structures of a series of bis-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)alkanes, compounds 5 to 9, have been determined by single crystal X-ray diffraction analysis. The structural parameters of the triazinone rings in the five compounds do not display systematic differences with respect to those reported for a few analogous compounds. The benzotriazinone rings in 5 and 9 are almost perpendicular to the alkylic chain. The molecules in the crystal packing are linked by means of a weak C-H···X H-bond (X = N/O). Compound 6 has two independent molecules in the asymmetric unit; one of the molecules displays disorder within the benzotriazinone moiety linked in position 1 to the propane alkylic group. The disordered molecule displays two conformations of the benzotriazinone linked in position 1 to the propane bridge. Compound 8 also displays disorder within the benzotriazinone moiety linked in position 1 to the pentane alkylic spacer group. The molecules of compound 7, in the crystal packing, also form intra and inter-molecular C-H···X (X = N/O) hydrogen bonds. None of these compounds show any tendency to adopt a folded conformation with intramolecular π-π stacking between benzotriazinone units. Crystal data: 5 CHNO monoclinic, space group P2 /c, a = 4.8370(2)Å, b = 14.7845(7)Å, c = 10.0837(4)Å, β = 95.430(2)°, V = 717.88(6)Å, for Ζ = 2; 6 CHNO triclinic, space group P- 1, a = 7.4237(4)Å, b = 14.4738(9)Å, c = 15.0359(10)Å, α = 91.871(3)°, β = 92.147(3)°, γ = 101.233(3)°, V = 1582.2(2)Å, for Ζ = 4; 7 CHNO monoclinic, space group C2/c, a = 33.8886(10)Å, b = 6.4593(2)Å, c = 16.0608(6)Å, β = 102.298(1)°, V = 3435.0(2)Å, for Ζ = 8; 8 CHNO triclinic, space group P- 1, a = 7.2592(2)Å, b = 7.6795(2)Å, c = 16.1003(5)Å, α = 85.292(1)°, β = 81.367(1)°, γ = 88.377(1)°, V = 884.26(4)Å, for Ζ = 2; 9 CHNO monoclinic, space group P2 /c, a = 7.2668(2)Å, b = 4.5612(1)Å, c = 28.1993(12)Å, β = 97.313(2)°, V = 927.07(5)Å, for Ζ = 2. Graphical Abstract: The crystal structures of a series of bis-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)alkanes have been determined by single crystal X-ray diffraction analysis.[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1. [Copyright &y& Elsevier]