Alpha-glucosidase activity of novel pyrazolobenzothiazine 5,5-dioxide derivatives for the treatment of diabetes mellitus. Invitro combined with molecular docking approach

Abstract

Diabetes mellitus is a metabolic disease caused due to the improper secretion of insulin which leads to hyperglycaemia. According to the International Diabetes Federation (IDF), 371 million people are affected by diabetes worldwide, while 7 million people are suffering from this disease in Pakistan. Pyrazolobenzothiazine 5,5-dioxide derivatives have anti-bacterial, anti-inflammatory, antioxidant activity and have the potential to treat diabetes and other diseases. This study was designed to perform in-silico and in-vitro analysis of pyrazolobenzothiazine 5,5-dioxide derivatives against αglucosidase for the treatment of diabetes mellitus. For this purpose, pyrazolobenzothiazine 5,5-dioxide derivatives were synthesized in the laboratory. Molecular docking analysis of pyrazolobenzothiazine 5,5-dioxide derivatives against αglucosidase was achieved through Molecular Operating Environment (MOE) and ranked them based on binding affinity. Compounds with strong binding interaction were selected for invitro anti-diabetic analysis by enzyme inhibition assay against αglucosidase using p-nitrophenyl-α-Dglucopyranoside (PNPG) as a substrate. Furthermore, the dose-response analysis was performed via Microdilution method. Compounds having strong bonding interactions with the active site and high scores were selected for in-vitro analysis. Compounds 1a, 1f, 1 g, 1 h showed strong bonding interaction with the active site of αglucosidase and have docking score − 11.303, −10.189, −10.360, −10.160 respectively. Compound 1e, 1f, 1 g and 1 h showed IC50 at the concentration of 4.7 μM, 8.8 μM, 12.2 μM and 11.2 μM respectively in ezyme inhibition assay. The outcome of this study proved helpful to determine new antidiabetic agents to minimize diabetes complication.

Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl]-N-arylacetamides: An In Silico and Biochemical Approach

“…Similarly, various 1,2-benzothiazine 1,1-dioxides have been reported as antileukemic [25][26][27], 11β-HSD1 inhibitors [28], endotheline receptor antagonists [29], antimalarial agents [30], MAO inhibitors [31], antiallergic agents [32], antithrombotics [33], antiparasitic [34], antimicrobials [35,36], antioxidants [37], inhibitors of calpain I [38], and aldose reductase enzymes [39,40]. Our research group is involved in the search for novel and more effective antidiabetic agents [41][42][43][44][45], and in this context we have synthesized novel 1,2-benzothiazine-N-arylacetamides and screened them for their in silico and in vitro α-glucosidase inhibitory potential.…”

“…Our research group is involved in the search for novel and more effective antidiabetic agents [41][42][43][44][45], and in this context we have synthesized novel 1,2-benzothiazine-Narylacetamides and screened them for their in silico and in vitro α-glucosidase inhibitory potential.…”

“…Among all the compounds, 11c, 12a, 12d, 12e, and 12g showed the most promising α-glucosidase inhibition with IC 50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 µM, respectively (Table 1). These inhibitors have IC 50 values even less than the standard drug, acarbose (58.8 µM [42,43]). These compounds showed more potent α-glucosidase inhibitions compared to the previously reported sulfonamides [63], dihydroxy pyrrolidines [64], and thiobarbituric acid enamine derivatives [65].…”

N‐Substituted pyrimidinethione and acetophenone derivatives as a new therapeutic approach in diabetes

“…A hydrophobic contact between Trp376, Ile441, Trp516, Met519, Trp613, and Phe649 residues results in the stabilization. [32] Taj et al [33] have reported that pyrazolobenzothiazine 5,5-dioxide derivatives inhibit Asp203, Asp542, Asp327, His600, and Arg526 residues of human maltase-glucoamylase enzyme that is related to the human α-glycosidase.…”

Recent Advances in Synthesis and Medicinal Evaluation of 1,2‐Benzothiazine Analogues

“…During our contemplation on this paper, we get to know that combination of two structurally different but biologically and medicinally active scaffolds can lead to revolutionary hike in their potency when compare to their individual influence. For instance, combination of 1,2-benzothiazine with pharmaceutically active derivatives of quinolones, [64] piprazine, [36][37]54,56,62] azoyls, [65][66] and pyrazoles [58,72,75,[78][79][80][81]83,[88][89] lead to even more active compounds which makes the researchers job easier to invent superior drug candidate. Also, performance of 1,2benzothiazines increases when they exist in complex forms with metals like Copper (II), Zinc (II), Nickel (II), Cobalt (II) and Ruthenium (III), [50][51][52][53] with enhanced pharmacokinetics and reduces side effects.…”