Identification of Cyclicsulfonamide Derivatives with an Acetamide Group as 11.BETA.-Hydroxysteroid Dehydrogenase 1 Inhibitors

Abstract

In the continuation of our 11b b-hydroxysteroid dehydrogenase type 1 (11b b-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11b b-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11b b-HSD1, selectivity against 11b b-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11b b-HSD1.

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

“…All the synthesized derivatives were well characterized with 1 H-NMR, 13 C-NMR, and MS spectroscopic techniques. In the 1 H-NMR spectra, the methylene (CH 2 ) protons appeared as a singlet at 3.95-4.20 ppm and the observation was consistent with literature values of similar compounds [46,49]. The methyl protons (CH 3 ) and methoxy protons appeared as singlets at 1.96-2.17 and 3.64-3.86 ppm, respectively.…”

“…The NH and enolic-OH protons were observed as singlets at 9.16-10.54 and 14.92-15.18 ppm, respectively [37,49,50]. Peaks for enolic-OH protons were not observed in some spectra due to the exchangeable nature of OH protons [49]. All the peak values from 6.50-8.50 ppm were assigned to aromatic protons.…”

“…In 2011, Kim and colleagues synthesized different 1,2-benzothiazine-N-arylacetamides and screened them for their in vitro inhibition toward human 11β-HSD1. The derivative 3 (Figure 1) showed the most promising activity with an IC 50 value of 0.041 µM [49]. Recently, Shin and coworkers reported novel 1,2-benzothiazine-N-arylacetamides as SARS-CoV-2 inhibitors and among them compound 4 (Figure 1) showed robust activity with an IC 50 value of 0.88 µM [51].…”

Identification of Cyclic Sulfonamides with an N-Arylacetamide Group as α-Glucosidase and α-Amylase Inhibitors: Biological Evaluation and Molecular Modeling

“…After the discovery of these biologically potent scaffolds, numerous 1,2-benzothiazine 1,1-dioxides were synthesized and reported to have significant pharmacological activities. For example, 1,2-benzothiazine-N-arylacetamides 3 and 4 (Figure 1) were found to be good inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with IC 50 values of 0.041 and 0.88 µM, respectively [26,27]. Similarly, the derivative 5 (Figure 1) exhibited excellent inhibition of aldose reductase enzymes, with an IC 50 value of 0.11 µM [28].…”

Design, Synthesis, and in vitro Evaluation of Tubulin‐Targeting Dibenzothiazines with Antiproliferative Activity as a Novel Heterocycle Building Block

“…[38] Applying this methodology, we transformed the flexible conformation of the N-aryl-benzenesulfonamides into a fused aromatic system, resulting in a structurally rigid analogue. On to other hand, the skeleton of the dibenzothiazines is constituted by the 1,2 benzothiazine 1,1-dioxide building block, which presents a wide variety of biological activities, including antihepatitis C virus (HCV), [39,40] 11β-HSD1 inhibitors, [41,42] anti-HIV and anticancer. [43,44] The aim of this work is the design and synthesis of several (di)benzothiazine derivatives to explore these scaffolds as building blocks of potentially biological active compounds.…”