Design, Synthesis and Biological Evaluation of N4-Sulfonamido-Succinamic, Phthalamic, Acrylic and Benzoyl Acetic Acid Derivatives as Potential DPP IV Inhibitors

As incidence rate of type II diabetes mellitus continues to rise, there is a growing need to identify novel therapeutic agents with improved efficacy and reduced side effects. Dipeptidyl peptidase IV (DPP IV) is a multifunctional protein involved in many physiological processes. It deactivates the natural hypoglycemic incretin hormone effect. Inhibition of this enzyme increases endogenous incretin level, incretin activity and should restore glucose homeostasis in type II diabetic patients making it an attractive target for the development of new antidiabetic drugs. One of the interesting reported anti- DPP IV hits is Gemifloxacin which is used as a lead compound for the development of new DPP IV inhibitors. In the current work, design and synthesis of a series of N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives was carried out. The synthesized compounds were evaluated for their in vitro anti-DPP IV activity. Some of them have shown reasonable bioactivity, where the most active one 17 was found to have an IC50 of 33.5 μM.

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Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

Current Computer - Aided Drug Design ◽

10.2174/1573409916666201007124122 ◽

2020 ◽

Vol 16 ◽

Author(s):

Reema Abu Khalaf ◽

Shorooq Alqazaqi ◽

Maram Aburezeq ◽

Dima Sabbah ◽

Ghadeer Albadawi ◽

...

Keyword(s):

Inhibitory Activity ◽

Biological Evaluation ◽

Ligand Docking ◽

Biological Assessment ◽

Hypoglycemic Agents ◽

Binding Affinities ◽

Oral Hypoglycemic Agents ◽

Design Synthesis ◽

Dpp Iv

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

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Design and Synthesis of 2-Mercapto Benzoxazole coupled Benzyl Triazoles as Anti-inflammatory Agents Targeting COX-2 Enzyme

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22956 ◽

2020 ◽

Vol 32 (12) ◽

pp. 3209-3218

Author(s):

K. Praveen Kumar ◽

Y. Prashanthi ◽

G. Rambabu ◽

Md. Ataur Rahman ◽

J.S. Yadav

Keyword(s):

Chemical Space ◽

Biological Evaluation ◽

Inflammatory Activity ◽

Design Synthesis ◽

Standard Drug ◽

Design And Synthesis ◽

Cox 2 ◽

Anti Inflammatory

In this study, we report the design, synthesis and the biological evaluation of 19 analogues of 2-mercapto benzoxazole coupled benzyl triazoles (BOTs) based on analysis of the binding site and literature of chemical space. These BOTs were evaluated both in vitro and in vivo for their anti-inflammatory activity. Eleven compounds showed less than 10 μM in vitro COX-2 enzyme activities. The most potent analogue among the BOT analogues were BOT15, BOT3 and BOT19 with IC50 3.40 μM, 4.50 μM and 4.57 μM respectively against COX-2. The in vivo anti-inflammatory activity of two BOTs has significantly higher than that of standard drug, ibuprofen. 2-Mercapto benzoxazole coupled benzyl triazoles (BOTs) were also tested for their antioxidant capacity and proved to be an as active scavenger, better than ascorbic acid.

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Enhanced cAMP generation and insulin-releasing potency of two novel Tyr1-modified enzyme-resistant forms of glucose-dependent insulinotropic polypeptide is associated with significant antihyperglycaemic activity in spontaneous obesity-diabetes

Biochemical Journal ◽

10.1042/bj20020319 ◽

2002 ◽

Vol 367 (3) ◽

pp. 913-920 ◽

Cited By ~ 26

Author(s):

Victor A. GAULT ◽

Peter R. FLATT ◽

Clifford J. BAILEY ◽

Patrick HARRIOTT ◽

Brett GREER ◽

...

Keyword(s):

Type Ii Diabetes ◽

Chinese Hamster ◽

Area Under The Curve ◽

Fold Increase ◽

Type Ii Diabetes Mellitus ◽

Type Ii ◽

Dpp Iv ◽

Camp Generation

Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin hormone, which potentiates glucose-induced insulin secretion. Antihyperglycaemic actions of GIP provide significant potential in Type II diabetes therapy. However, inactivation of GIP by the enzyme dipeptidyl peptidase IV (DPP IV) and its consequent short circulating half-life limit its therapeutic use. Therefore two novel Tyr1-modified analogues of GIP, N-Fmoc-GIP (where Fmoc is 9-fluorenylmethoxycarbonyl) and N-palmitate-GIP, were synthesized and tested for metabolic stability and biological activity. Both GIP analogues were resistant to degradation by DPP IV and human plasma. In Chinese hamster lung (CHL) cells expressing the cloned human GIP receptor, both analogues exhibited a 2-fold increase in cAMP-generating potency compared with native GIP (EC50 values of 9.4, 10.0 and 18.2nM respectively). Using clonal BRIN-BD11 cells, both analogues demonstrated strong insulinotropic activity compared with native GIP (P<0.01 to P<0.001). In obese diabetic (ob/ob) mice, administration of N-Fmoc-GIP or N-palmitate-GIP (25nmol/kg) together with glucose (18mmol/kg) significantly reduced the peak 15min glucose excursion (1.4- and 1.5-fold respectively; P<0.05 to P<0.01) compared with glucose alone. The area under the curve (AUC) for glucose was significantly lower after administration of either analogue compared with glucose administered alone or in combination with native GIP (1.5-fold; P<0.05). This was associated with a significantly greater AUC for insulin (2.1-fold; P<0.001) for both analogues compared with native GIP. A similar pattern of in vivo responsiveness was evident in lean control mice. These data indicate that novel N-terminal Tyr1 modification of GIP with an Fmoc or palmitate group confers resistance to degradation by DPP IV in plasma, which is reflected by increased in vitro potency and greater insulinotropic and antihyperglycaemic activities in an animal model of Type II diabetes mellitus.

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The effect of Milgamma NR and SperminR on in vitro cellular immune reactions in patients with type II diabetes mellitus

Immunology Letters ◽

10.1016/s0165-2478(97)88807-4 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 482

Author(s):

M Horváth

Keyword(s):

Diabetes Mellitus ◽

Type Ii Diabetes ◽

Type Ii Diabetes Mellitus ◽

Type Ii ◽

Immune Reactions ◽

Cellular Immune

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Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

Letters in Organic Chemistry ◽

10.2174/1570178616666190408101233 ◽

2019 ◽

Vol 16 (10) ◽

pp. 837-845

Author(s):

Sandhya Jonnala ◽

Bhaskar Nameta ◽

Murthy Chavali ◽

Rajashaker Bantu ◽

Pallavi Choudante ◽

...

Keyword(s):

Molecular Docking ◽

Inhibitory Activity ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Mouse Skin ◽

Coupling Reaction ◽

Binding Mode ◽

Biological Evaluation ◽

Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

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DPP-IV Inhibitory Phenanthridines: Ligand, Structure-Based Design and Synthesis

Current Computer - Aided Drug Design ◽

10.2174/1573409915666181211114743 ◽

2020 ◽

Vol 16 (3) ◽

pp. 295-307

Author(s):

Reema A. Khalaf ◽

Dalal Masalha ◽

Dima Sabbah

Keyword(s):

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Ligand Docking ◽

Health Concern ◽

Aromatic Rings ◽

Oral Antidiabetic Agents ◽

Design And Synthesis ◽

Dpp Iv ◽

Novel Scaffold

Background: Lately, diabetes has become the main health concern for millions of people around the world. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new class of oral antidiabetic agents. Formerly, acridines, N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives, and sulfamoyl-phenyl acid esters were designed and developed as new DPP-IV inhibitors. Objective: This study aims to develop a pharmacophore model of DPP-IV inhibitors and to evaluate phenanthridines as a novel scaffold for inhibiting DPP-IV enzyme. In addition, to assess their binding interactions with the enzyme through docking in the binding site of 4A5S (PDB). Methods: Herein, Quantum–Polarized Ligand Docking (QPLD) and ligand-based pharmacophore modeling investigations were performed. Three novel 3,8-disubstituted-6-phenyl phenanthridine derivatives 3-5 have been designed, synthesized and characterized. In vitro biological testing against DPP-IV was carried out using fluorometric assay kit. Results: QPLD study demonstrates that compounds 3-5 forms H-bond with Lys554, Trp629, and Tyr631, besides charge transfer interaction between their aromatic rings and the aromatic rings of Tyr547 and Tyr666. Moreover, they fit the three pharmacophoric point features of DPP-IV inhibitors and were proven to have in vitro DPP-IV inhibitory activity where compound 5 displayed a % inhibition of 45.4 at 100 μM concentration. Conclusion: Phenanthridines may serve as a potential lead compound for developing new DPP-IV inhibitors as a promising antidiabetic agent. Computational results suggest future structural simplification.

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A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

Nature Communications ◽

10.1038/s41467-021-23448-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Guodong Li ◽

Chung-Nga Ko ◽

Dan Li ◽

Chao Yang ◽

Wanhe Wang ◽

...

Keyword(s):

Wound Healing ◽

Small Molecule ◽

Hypoxia Inducible Factor ◽

Diabetic Patients ◽

Diabetic Mice ◽

Impaired Wound Healing ◽

Von Hippel Lindau ◽

Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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Discovery of new phenyl sulfonyl-pyrimidine carboxylate derivatives as the potential multi-target drugs with effective anti-Alzheimer’s action: Design, synthesis, crystal structure and in-vitro biological evaluation

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2021.113224 ◽

2021 ◽

Vol 215 ◽

pp. 113224

Author(s):

Shoaib Manzoor ◽

Santosh Kumar Prajapati ◽

Shreyasi Majumdar ◽

Kausar Raza ◽

Moustafa T. Gabr ◽

...

Keyword(s):

Crystal Structure ◽

Biological Evaluation ◽

Design Synthesis

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Design, Synthesis and Biological Evaluation of Novel Benzothiazole Based [1,2,4]Triazolo[4,3-c]quinazoline Derivatives

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22453 ◽

2020 ◽

Vol 32 (3) ◽

pp. 580-586

Author(s):

Ranjit V. Gadhave ◽

Bhanudas S. Kuchekar

Keyword(s):

Biological Evaluation ◽

Bacterial Strains ◽

Active Compounds ◽

Design Synthesis ◽

Structural Modifications ◽

E Coli ◽

Chemical Structures ◽

Ft Ir ◽

Antioxidant Agent

A new series of N-(benzo[d]thiazol-2-yl)-[1,2,4]triazolo[4,3-c]quinazoline-5-carboxamide derivatives were synthesized by condensation of [1,2,4]triazolo[4,3-c]quinazoline-5-carboxylate derivatives with substituted benzothiazoles. The chemical structures of the synthesized compounds were confirmed by FT-IR, MS and 1H NMR spectra. Designed triazoloquinazoline derivatives were docked with oxido-reductase enzyme (PDB Code 4h1j) and DNA gyrase enzyme (PDB Code 3g75). Based on high binding affinity score, the best compound were selected for synthesis and subjected to in vitro antioxidant and antibacterial activity. Compounds 7a and 7d were found to be most active compounds as antioxidant agent among this series when compared with ascorbic acid. Compounds 7a, 7d and 7f were found to be most active compounds as an antibacterial agents among this series when compared with ciprofloxacin against bacterial strains such as S. aureus (ATCC 25923), E. coli (ATCC 25922) and P. aeruginosa (ATCC 27853). Study revealed that the most active compounds after structural modifications can be exploited as lead molecules for other pharmacological activities such as anti-inflammatory, anticancer and antidepressant activities.

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