Abstract
Methods of 1-[2-(1H-tetrazol-5-yl)-R1-phenyl]-3-R2-phenyl(ethyl)ureas and R1-tetrazolo[1,5-c]quinazolin-5(6H)-ones synthesis were designed. IR, LC-MS, 1H NMR, and elemental analysis data evaluated the structure and purity of the obtained compounds. Different products, depending on the reaction conditions, were distinguished and discussed. The preliminary hypoglycemic activity of 36 synthesized compounds was revealed. Docking studies to 11β-hydroxysteroid dehydrogenase 1, γ-peroxisome proliferator-activated receptor, and dipeptidyl peptidase-4 were conducted. Eight of these substances were further tested on glucocorticoid-induced insulin resistance models, namely glucose tolerance, oral rapid insulin, and adrenalin tests. One of the most active compounds turned out to be tetrazolo[1,5-c]quinazolin-5(6H)-one 3.1, exceeding the reference drugs Metformin (50 and 200 mg/kg) and Gliclazide (50 mg/kg).
Highlights
Oral drugs used to treat type 2 diabetes mellitus (T2DM) are divided into six big groups: biguanides (e.g. Metformin), sulfonylureas (e.g. Glimepiride), meglitinides (e.g. Repaglinide), thiazolidinediones (e.g. Pioglitazone), dipeptidyl peptidase IV inhibitors (DPP4, e.g. Linagliptin), and α-glucosidase inhibitors (e.g. Acarbose)
Synthesis and in vivo studies of hypoglycemic activity among tetrazolebearing N-glycosides (D) as sodium-glucose co-transporter 2 (SGLT2) inhibitors were made by Kumari B. et al and Y L Gao et al (Fig. 1) [4, 5]
N-4(substituted phenyl)-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}-1,3,4-thiadiazol-2-amine derivatives according to docking glide score showed a high potency with regards to hypoglycemic activity [9]
Summary
Oral drugs used to treat type 2 diabetes mellitus (T2DM) are divided into six big groups: biguanides (e.g. Metformin), sulfonylureas (e.g. Glimepiride), meglitinides (e.g. Repaglinide), thiazolidinediones (e.g. Pioglitazone), dipeptidyl peptidase IV inhibitors (DPP4, e.g. Linagliptin), and α-glucosidase inhibitors (e.g. Acarbose). The most commonly used drugs with the exception of insulin can reduce the HbA1c level by just 1%. A solution to this problem can be found in the creation of combinatorial drugs or drugs with an entirely new mechanism of action These drugs must be able to provide prolonged hypoglycemic effects and influence the symptoms, and their causes. Some efforts for this approach were made by Yu Momose and coauthors, with their 5-(4alkoxyphenylalkyl)-1H-tetrazoles, with the best one being A, which showed potent glucose- and lipid-lowering activities in KKAy mice (Fig. 1) [1]. N-4(substituted phenyl)-5-{[(2-phenylquinazolin-4-yl)-oxy]-methyl}-1,3,4-thiadiazol-2-amine derivatives according to docking glide score showed a high potency with regards to hypoglycemic activity [9]
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