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Benzimidazole Bearing Thiosemicarbazone Derivatives Act as Potent α-Amylase and α-Glucosidase Inhibitors; Synthesis, Bioactivity Screening and Molecular Docking Study.

ABSTRACT: Diabetes mellitus is one of the most chronic metabolic diseases. In the past few years, our research group has synthesized and evaluated libraries of heterocyclic analogs against α-glucosidase and α-amylase enzymes and found encouraging results. The current study comprises the evaluation of benzimidazole-bearing thiosemicarbazone as antidiabetic agents. A library of fifteen derivatives (7-21) was synthesized, characterized via different spectroscopic techniques such as HREI-MS, NMR, and screened against α-glucosidase and α-amylase enzymes. All derivatives exhibited excellent to good biological inhibitory potentials. Derivatives 19 (IC₅₀ = 1.30 ± 0.20 µM and 1.20 ± 0.20 µM) and 20 (IC₅₀ = 1.60 ± 0.20 µM and 1.10 ± 0.01 µM) were found to be the most potent among the series when compared with standard drug acarbose (IC₅₀ = 11.29 ± 0.07 and 11.12 ± 0.15 µM, respectively). These derivatives may potentially serve as the lead candidates for the development of new therapeutic representatives. The structure-activity relationship was carried out for all molecules which are mainly based upon the pattern of substituent/s on phenyl rings. Moreover, in silico docking studies were carried out to investigate the active binding mode of selected derivatives with the target enzymes.

SUBMITTER: Ullah H

PROVIDER: S-EPMC9609971 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Benzimidazole Bearing Thiosemicarbazone Derivatives Act as Potent α-Amylase and α-Glucosidase Inhibitors; Synthesis, Bioactivity Screening and Molecular Docking Study.

Ullah Hayat H Khan Shoaib S Khan Shoaib S Rahim Fazal F Taha Muhammad M Iqbal Rashid R Sarfraz Maliha M Shah Syed Adnan Ali SAA Sajid Muhammad M Awad Mohamed F MF Omran Awatif A Albalawi Marzough Aziz MA Abdelaziz Mahmoud A MA Al Areefy Azza A Jafri Ibrahim I

Molecules (Basel, Switzerland) 20221015 20

Diabetes mellitus is one of the most chronic metabolic diseases. In the past few years, our research group has synthesized and evaluated libraries of heterocyclic analogs against α-glucosidase and α-amylase enzymes and found encouraging results. The current study comprises the evaluation of benzimidazole-bearing thiosemicarbazone as antidiabetic agents. A library of fifteen derivatives (<b>7</b>-<b>21</b>) was synthesized, characterized via different spectroscopic techniques such as HREI-MS, NMR ...[more]

PMID: 36296520

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Project description:There is an increasing prevalence of diabetes mellitus throughout the world, and new compounds are necessary to combat this. The currently available antidiabetic therapies are long-term complicated and side effect-prone, and this has led to a demand for more affordable and more effective methods of tackling diabetes. Research is focused on finding alternative medicinal remedies with significant antidiabetic efficacy as well as low adverse effects. In this research work, we have focused our efforts to synthesize a series of 1,2,4-triazole-based bis-hydrazones and evaluated their antidiabetic properties. In addition, the precise structures of the synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H-NMR, 13C-NMR, and HREI-MS. To find the antidiabetic potentials of the synthesized compounds, in vitro α-glucosidase and α-amylase inhibitory activities were characterized using acarbose as the reference standard. From structure-activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both α-amylase and α-glucosidase enzymes was due to the different substitution patterns of the substituent(s) at variable positions of both aryl rings A and B. The results of the antidiabetic assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values ranging from 0.70 ± 0.05 to 35.70 ± 0.80 μM (α-amylase) and 1.10 ± 0.05 to 30.40 ± 0.70 μM (α-glucosidase). The obtained results were compared to those of the standard acarbose drug (IC50 = 10.30 ± 0.20 μM for α-amylase and IC50 = 9.80 ± 0.20 μM for α-glucosidase). Specifically, compounds 17, 15, and 16 were found to be significantly active with IC50 values of 0.70 ± 0.05, 1.80 ± 0.10, and 2.10 ± 0.10 μM against α-amylase and 1.10 ± 0.05, 1.50 ± 0.05, and 1.70 ± 0.10 μM against α-glucosidase, respectively. These findings reveal that triazole-containing bis-hydrazones act as α-amylase and α-glucosidase inhibitors, which help develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic agents.

Project description:Diabetes mellitus (DM) is one of the most dangerous metabolic diseases with a high rate of mortality worldwide. It is well known that insulin resistance and deficiency in insulin production from pancreatic β-cells are the main characteristics of DM. Due to the detrimental side effects of the current treatment, there is a considerable need to develop new effective antidiabetic drugs, especially alpha-glucosidase and alpha-amylase inhibitors with lesser adverse effects. These inhibitors are known to be directly involved in the delay of carbohydrate digestion, resulting in a reduction of glucose absorption rate and, consequently, reducing the postprandial rise of plasma glucose, which can reduce the risk of long-term diabetes complications. Furthermore, natural products are well-known sources for the discovery of new bioactive compounds that can serve as scaffolds for drug discovery, including that of new antidiabetic drugs. The phytochemical investigation of Salvia aurita collected from Hogobach Pass, Eastern Cape Province, South Africa (SA), yielded four known abietane diterpenes namely carnosol (1), rosmanol (2), 7-methoxyrosmanol (3), 12-methoxycarnosic acid (4), and one flavonoid named 4,7-dimethylapigenin (5). Structural characterization of these isolated compounds was conducted using 1 and 2D NMR, in comparison with reported spectroscopic data. These compounds are reported for the first time from S. aurita. The biological evaluation of the isolated compound against alpha-glucosidase exhibited strong inhibitory activities for 3 and 2 with the half maximal inhibitory concentration (IC50) values of 4.2 ± 0.7 and 16.4 ± 1.1 µg/mL respectively, while 4 and 1 demonstrated strong alpha-amylase inhibitory activity amongst the isolated compounds with IC50 values of 16.2 ± 0.3 and 19.8 ± 1.4 µg/mL. Molecular docking analysis confirms the strong inhibitory activity of 3 against alpha-glucosidase. Additionally, excellent antioxidant capacities were displayed by 2, 1, and 3, respectively, with oxygen radical absorbance capacity (ORAC) (25.79 ± 0.01; 23.96 ± 0.01; 23.94 ± 0.02) mM Trolox equivalent (TE)/g; 1 and 2 as ferric-ion reducing antioxidant power (FRAP) (3.92 ± 0.002; 1.52 ± 0.002) mM ascorbic acid equivalent (AAE)/g; 5 and 2 as Trolox equivalent absorbance capacity (TEAC) (3.19 ± 0.003; 2.06 ± 0.003) mM TE/g. The methanolic extract of S. aurita is a rich source of abietane diterpenes with excellent antioxidant and antidiabetic activities that can be useful to modulate oxidative stress and might possibly be excellent candidates for the management of diabetes. This is the first scientific report on the phytochemical isolation and biological evaluation of the alpha-glucosidase and alpha-amylase inhibitory activities of Salvia aurita.

Dataset Information

Benzimidazole Bearing Thiosemicarbazone Derivatives Act as Potent α-Amylase and α-Glucosidase Inhibitors; Synthesis, Bioactivity Screening and Molecular Docking Study.

Publications

Benzimidazole Bearing Thiosemicarbazone Derivatives Act as Potent α-Amylase and α-Glucosidase Inhibitors; Synthesis, Bioactivity Screening and Molecular Docking Study.

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