Synthesis of Pyrazolo[1,2-b]phthalazine-5,10- dione Derivatives: A New Class of α –Glucosidase Inhibitors

Background: Hyperglycemia is a metabolic disorder that refers to an increase in blood sugar in diabetic patients. α-Glucosidase has been introduced as a membrane-bound enzyme, and it is the main enzyme for carbohydrate digestion in some parts of the intestine. Inhibition of α -glucosidase enzyme activity is a reliable approach to control post-prandial hyperglycemia condition. Objectives: In this study, a series of Pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 5a–t were synthesized via a multicomponent reaction and evaluated as new inhibitors for α-glucosidase. Methods: The biological activity of the synthesized compounds was studied using a source of the α-glucosidase enzyme (EC3.2.1.20, Saccharomyces cerevisiae) at 20 U/mg concentration. Results: Four compounds showed higher α-glucosidase inhibitory activity in comparison to a standard, i.e., Acarbose. Compound 5q displays the most potent α-glucosidase inhibitory activity (IC50 = 155.4 ± 6.0 μM). Conclusion: In conclusion, some of the synthesized compounds, including heterocyclic core molecules, have shown remarkable activity that could be considered as subjects for the development of new, more efficient inhibitors of the α-glucosidase enzyme.

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Synthesis, Molecular Docking and α-Glucosidase Inhibitory Activity Study of 2,4,6-triaryl Pyrimidine Derivatives

Letters in Drug Design & Discovery ◽

10.2174/1570180817666200103130536 ◽

2020 ◽

Vol 17 (10) ◽

pp. 1216-1226

Author(s):

Mohammed Hussen Bule ◽

Roghaieh Esfandyari ◽

Tadesse Bekele Tafesse ◽

Mohsen Amini ◽

Mohammad Ali Faramarzi ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Molecular Docking ◽

Inhibitory Activity ◽

Abdominal Distension ◽

Spectroscopic Techniques ◽

Pyrimidine Derivatives ◽

Molecular Docking Study ◽

Enzyme Active Site ◽

Glucosidase Inhibitors

Background: α-Glucosidase inhibitors hinder the carbohydrate digestion and play an important role in the treatment of diabetes mellitus. α-glucosidase inhibitors available on the market are acarbose, miglitol, and voglibose. However, the use of acarbose is diminishing due to related side effects like diarrhea, bloating and abdominal distension. Objectives: This study aimed to synthesize 2,4,6-triaryl pyrimidines derivatives, screen their α- glucosidase inhibitory activity, perform kinetic and molecular docking studies. Methods: A series of 2,4,6-triaryl pyrimidine derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Pyrimidine derivatives 4a-m were synthesized via a twostep reaction with a yield between 49 and 93%. The structure of the synthesized compounds was confirmed by different spectroscopic techniques (IR, NMR and MS). The in vitro α-glucosidase inhibition activities of the synthesized compounds 4a-m was also evaluated against Saccharomyces cerevisiae α-glucosidase. Results and Discussion: The majority of synthesized compounds had α-glucosidase inhibitory activity. Particularly compounds 4b and 4g were the most active compounds with an IC50 value of 125.2± 7.2 and 139.8 ± 8.1 μM respectively. The kinetic study performed for the most active compound 4b revealed that the compound was a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 μM. The molecular docking study also revealed that the two compounds have important binding interactions with the enzyme active site. Conclusion: 2,4,6-triarylpyrimidine derivative 4a-m were synthesized and screened for α- glucosidase inhibitory activity. Most of the synthesized compounds possess α-glucosidase inhibitory activity, and compound 4b demonstrated the most significant inhibitory action as compared to acarbose.

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Intestinal α-Glucosidase Inhibitors in Achillea millefolium

Natural Product Communications ◽

10.1177/1934578x1701200828 ◽

2017 ◽

Vol 12 (8) ◽

pp. 1934578X1701200

Author(s):

Kota Noda ◽

Eisuke Kato ◽

Jun Kawabata

Keyword(s):

Enzyme Activity ◽

Bioactive Compounds ◽

Inhibitory Activity ◽

Achillea Millefolium ◽

Major Contributor ◽

Caffeoylquinic Acids ◽

Glucosidase Inhibitor ◽

Glucosidase Inhibitors ◽

Prevention And Treatment ◽

Treatment Of Diabetes

Achillea millefolium is a plant used as a component of anti-diabetic preparation but the bioactive compounds responsible for its use are not known. Inhibition of intestinal α-glucosidase is a preferable effect for prevention and treatment of diabetes, and A. millefolium extract showed inhibitory activity against the enzyme. Activity-guided separation of the extract gave four mono- or di-caffeoylquinic acids as the isolate. Quantitation of these four caffeoylquinic acids and the activity of the isolates suggested that these are the major contributor for the α-glucosidase inhibitory activity in the extract. However also, the presence of unidentified, minor, but potent α-glucosidase inhibitor in the isolate was also suggested.

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Spiroindolone Analogues as Potential Hypoglycemic with Dual Inhibitory Activity on α-Amylase and α-Glucosidase

Molecules ◽

10.3390/molecules24122342 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2342 ◽

Cited By ~ 6

Author(s):

Mezna Saleh Altowyan ◽

Assem Barakat ◽

Abdullah Mohammed Al-Majid ◽

H.A. Al-Ghulikah

Keyword(s):

Inhibitory Activity ◽

Type Ii Diabetes ◽

Addition Reaction ◽

Type Ii Diabetes Mellitus ◽

Docking Studies ◽

Type Ii ◽

Binding Interaction ◽

Enzyme Active Site ◽

Glucosidase Inhibitors ◽

Control Post

Inhibition of α-amylase and α-glucosidase by specified synthetic compounds during the digestion of starch helps control post-prandial hyperglycemia and could represent a potential therapy for type II diabetes mellitus. A new series of spiroheterocyclic compounds bearing oxindole/benzofuran/pyrrolidine/thiazolidine motifs were synthesized via a 1,3-dipolar cyclo-addition reaction approach. The specific compounds were obtained by reactions of chalcones having a benzo[b]furan scaffold (compounds 2a–f), with a substituted isatin (compounds 3a–c) and heterocyclic amino acids (compounds 4a,b). The target spiroindolone analogues 5a–r were evaluated for their potential inhibitory activities against the enzymes α-amylase and α-glucosidase. Preliminary results indicated that some of the target compounds exhibit promising α-amylase and α-glucosidase inhibitory activity. Among the tested spiroindolone analogues, the cycloadduct 5r was found to be the most active (IC50 = 22.61 ± 0.54 μM and 14.05 ± 1.03 μM) as α-amylase and α-glucosidase inhibitors, with selectivity indexes of 0.62 and 1.60, respectively. Docking studies were carried out to confirm the binding interaction between the enzyme active site and the spiroindolone analogues.

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Exterior and Interior Events in Early Stage of Thrombin-induced Platelet Aggregation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651878 ◽

1977 ◽

Vol 38 (03) ◽

pp. 0630-0639 ◽

Cited By ~ 4

Author(s):

Shuichi Hashimoto ◽

Sachiko Shibata ◽

Bonro Kobayashi

Keyword(s):

Molecular Weight ◽

Enzyme Activity ◽

Plasma Membrane ◽

Platelet Aggregation ◽

Early Stage ◽

Adenyl Cyclase ◽

Cellular Component ◽

Primary Event ◽

Rabbit Platelets ◽

Membrane Bound

SummaryTreatment of washed rabbit platelets with 1 u/ml of thrombin at 37° C resulted in a disappearance from platelets of a protein with 250,000 dalton molecular weight which was shown to be originated from plasma membrane. Parallel loss of adenyl cyclase was noted, and both reactions were complete within 30 sec. From the patterns of disc electrophoretograms, the importance of quick suppression of thrombin action in demonstrating the primary event was stressed.Thrombin induced an apparent activation of membrane bound phosphodiesterase. This reaction was also complete within 30 sec. The cellular component which contained the enzyme activity was distinct from plasma membrane. Soluble phosphodiesterase was not influenced by thrombin at all.These reactions required intact platelet cells to react with thrombin, and no reaction was detected when subcellular preparations were treated with thrombin.Possibility of collaboration of changes in externally located synthetic enzyme with those in internally located degrading enzyme in the early phase of thrombin action on platelets was suggested.

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Recent Developments in Alpha-Glucosidase Inhibitors for Management of Type-2 Diabetes: An Update

Current Pharmaceutical Design ◽

10.2174/1381612825666190717104547 ◽

2019 ◽

Vol 25 (23) ◽

pp. 2510-2525 ◽

Cited By ~ 5

Author(s):

Bashir Usman ◽

Neha Sharma ◽

Saurabh Satija ◽

Meenu Mehta ◽

Manish Vyas ◽

...

Keyword(s):

Type 2 Diabetes ◽

Patient Compliance ◽

Postprandial Hyperglycemia ◽

Diabetic Patients ◽

Poor Patient ◽

Glucosidase Inhibitors ◽

Poor Patient Compliance ◽

Recent Developments ◽

Alpha Glucosidase

The incidence of diabetes has increased globally in recent years and figures of diabetic patients were estimated to rise up to 642 million by 2040. The disorder is accompanied with various complications if not managed at the early stages, and interlinked high mortality rate and morbidity with time. Different classes of drugs are available for the management of type 2 diabetes but were having certain limitations of their safety. Alphaglucosidase is a family of enzyme originated from the pancreas which plays a role in the anabolism of 80-90% of carbohydrate consumed into glucose. This glucose is absorbed into the blood and results in frank postprandial hyperglycemia and worsens the conditions of diabetic patients which precipitate complications. Inhibition of these enzymes helps to prevent postprandial hyperglycemia and the formation of glycated end products. Alphaglucosidase inhibitors are reported to be more important in adequate control of type 2, but marketed drugs have various side effects, such as poor patient compliance and also expensive. This proves the needs for other class of drugs with better efficacy, safety, patient compliance and economic. In this review, we have emphasized the recent advances in the field of new alpha-glucosidase inhibitors with improved safety and pharmacological profile.

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Synthesis and biological activity of selenopsammaplin A and its analogues as antitumor agents with DOT1L inhibitory activity

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116072 ◽

2021 ◽

Vol 35 ◽

pp. 116072 ◽

Cited By ~ 1

Author(s):

Hae Ju Han ◽

Woong Sub Byun ◽

Gyu Ho Lee ◽

Won Kyung Kim ◽

Kyungkuk Jang ◽

...

Keyword(s):

Biological Activity ◽

Inhibitory Activity ◽

Antitumor Agents

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A NEW CLASS OF ACYCLIC NUCLEOSIDE PHOSPHONATES: SYNTHESIS AND BIOLOGICAL ACTIVITY OF 9-{[(PHOSPHONOMETHYL)AZIRIDIN-1-YL]METHYL}GUANINE (PMAMG) AND ANALOGUES

Nucleosides Nucleotides & Nucleic Acids ◽

10.1081/ncn-120015721 ◽

2002 ◽

Vol 21 (10) ◽

pp. 619-635 ◽

Cited By ~ 16

Author(s):

Ghassan Abu Sheikha ◽

Paolo La Colla ◽

Anna Giulia Loi

Keyword(s):

Biological Activity ◽

New Class ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside

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Genetic and Phenotypic Analyses of therdx Locus of Rhodobacter sphaeroides2.4.1

Journal of Bacteriology ◽

10.1128/jb.182.12.3475-3481.2000 ◽

2000 ◽

Vol 182 (12) ◽

pp. 3475-3481 ◽

Cited By ~ 15

Author(s):

Jung Hyeob Roh ◽

Samuel Kaplan

Keyword(s):

Gene Expression ◽

Rhodobacter Sphaeroides ◽

Redox Protein ◽

Deletion Mutations ◽

Metal Transporter ◽

New Class ◽

Mutant Strains ◽

Membrane Bound ◽

Photosynthesis Gene

ABSTRACT Previously, we reported that rdxB, encoding a likely membrane-bound two [4Fe-4S]-containing center, is involved in the aerobic regulation of photosystem gene expression in Rhodobacter sphaeroides 2.4.1. To further investigate the role ofrdxB as well as other genes of the rdxBHISoperon on photosystem gene expression, we constructed a series of nonpolar, in-frame deletion mutations in each of the rdxgenes. Using both puc and puf operonlacZ fusions to monitor photosystem gene expression, under aerobic conditions, in each of the mutant strains revealed significant increased photosynthesis gene expression. In the case of mutations in either rdxH, rdxI, or rdxS, the aerobic induction of photosystem gene expression is believed to be indirect by virtue of a posttranscriptional effect oncbb 3 cytochrome oxidase structure and integrity. For RdxB, we suggest that this redox protein has a more direct effect on photosystem gene expression by virtue of its interaction with the cbb 3 oxidase. An associated phenotype, involving the enhanced conversion of the carotenoid spheroidene to spheroidenone, is also observed in the RdxB, -H, -I, and -S mutant strains. This phenotype is also suggested to be the result of the role of the rdxBHIS locus incbb 3 oxidase activity and/or structure. RdxI is suggested to be a new class of metal transporter of the CPx-type ATPases.

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