Directed Search of Biologically Active Compounds among Hydrogenated Isoindolylalkyl(alkylaryl-,aryl-)carboxylic Acids with Quinazoline Fragment that Modify the Carbohydrate Metabolism: Design, Synthesis and Modification

Abstract

An effective synthesis of (3H-quinazoline-4-ylidene)hydrazides of N-carboxyalkyl-(arylalkyl-,aryl-)isoindoline-1,3-diones, using activated N-protected aminoacids and 4-hydrazinoquinazoline was proposed in the framework methodology of directed search of hypoglycemic agents (fragment-oriented design, molecular docking). These hydrazides prepared via cyclocondensation under acid catalysis were converted to the corresponding 2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl-) alkyl-(alkylaryl-,aryl-)-hydroisoindole-1,3(2H)-diones. The structure of synthesized compounds was established using IR, 1 H and 13 C NMR spectroscopy and LC-MS and the features of spectral pattern were discussed. The results of pharmacological screening revealed a series of compounds, that are short-acting hypoglycemic agents like prandial regulators of glucose (Mitiglinide). The SAR analysis showed, that the introduction of a hydrogenated 1,3-dioxoisoindole moiety bonded through linker groups with 4-hydrazinoquinazoline and triazolo[1,5-c]quinazoline cycles is reasonable in the context of searching for short-acting hypoglycemic agents and requires further research.

Quinazoline-containing Hydrazydes of Dicarboxylic Acids and Products of Their Structural Modification: A Novel Class of Anti-inflammatory Agents

“…Previously heterocyclization of corresponding (3H-quinazoline-4-ylidene)hydrazides was described as the most efficient and convenient method for 2-R- [1,2,4] triazolo [1,5-c]quinazolines synthesis. [1][2][3][4][5][6][7][8] The preparation of the above-mentioned hydrazides is based on the acylation of 4-hydrazinoquinazoline by anhydrides, acyl halides, N-acyl imidazolides and other highly reactive derivatives of carboxylic acids. [1][2][3] Namely, above-mentioned approaches were used for the synthesis of target compounds.…”

“…Such high potential of above-mentioned compounds caused by the possibility of chemical modification aimed to the introduction of diverse pharmacophore fragments. [1][2][3][4][5][6][7] Moreover, cyclisation of above-mentioned hydrazides yielded substituted triazolo [c]quinazolines that show a wide range of biological activity including anticonvulsant, antitumor, hypoglycemic, antibacterial and other activities. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Despite the numerous publications devoted to the chemistry and biology of hydrazides formed by quinazolin-4(3H)-ylidenehydrazine, some features of their formation, reactivity, physicochemical and biological properties have been insufficiently studied.…”