Potential Antidiabetic Agents Research Articles

Synthesis, in vitro α-glucosidase inhibitory activities, and molecular dynamic simulations of novel 4-hydroxyquinolinone-hydrazones as potential antidiabetic agents

In the present study, new structural variants of 4-hydroxyquinolinone-hydrazones were designed and synthesized. The structure elucidation of the synthetic derivatives 6a–o was carried out using different spectroscopic techniques including FTIR, 1H-NMR, 13C-NMR, and elemental analysis, and their α-glucosidase inhibitory activity was also determined. The synthetic molecules 6a–o exhibited good α-glucosidase inhibition with IC50 values ranging between 93.5 ± 0.6 to 575.6 ± 0.4 µM as compared to the standard acarbose (IC50 = 752.0 ± 2.0 µM). Structure–activity relationships of this series were established which is mainly based on the position and nature of the substituent on the benzylidene ring. A kinetic study of the active compounds 6l and 6m as the most potent derivatives were also carried out to confirm the mode of inhibition. The binding interactions of the most active compounds within the active site of the enzyme were determined by molecular docking and molecular dynamic simulations.

In silico molecular docking study and nano TiO2-SiO2 catalyzed microwave facilitated synthesis of new bis(α-aminophosphonates) as potential anti-diabetic agents

In the present work, we have developed a greener approach to synthesize a series of novel bis(α-aminophosphonates) (bis(α-Aps)) via a microwave-mediated nano TiO2-SiO2 catalyzed Kabachnik-Fields (K-F) reaction under solvent-free conditions. An in silico molecular docking analysis was performed on all the designed molecules prior to their synthesis to get insight into their capacity to block the enzymes, α-amylase (PDB ID:3IJ8) and α-glucosidase (PDB ID:1OBB). The molecules with significant binding affinity were synthesized and spectroscopically analyzed to confirm their structure. They were screened further in vitro for their inhibitory activity on the target enzymes. When compared with the reference drug, the compounds diethyl[(2H‐1,3‐benzodioxol‐5‐yl)[(6‐{[(2H‐1,3‐benzodioxol‐5‐yl)(diethoxyphosphoryl)-methyl]amino}‐10,10‐dioxo‐9H‐10λ6‐thioxanthen‐3‐yl)amino]-methyl]phosphonate (4h), diethyl [(anthracen-9-yl)[(6-{[(anthracen-9-yl)(diethoxyphosphoryl)methyl]amino}-10,10-dioxo-9H-10λ6-thioxanthen-3-yl)amino]-methyl]phosphonate (4i) have shown greater inhibition, and diethyl{[(6‐{[(diethoxyphosphoryl)(phenyl)methyl]amino}‐10,10‐dioxo‐9H‐10λ6‐thioxanthen‐3‐yl)amino](phenyl)methyl}phosphonate (4a), diethyl {[(6-{[(diethoxyphosphoryl)(4-hydroxy-3-nitrophenyl)methyl]amino}-10,10-dioxo-9H-10λ6-thioxanthen-3-yl)amino](4-hydroxy-3-nitrophenyl)methyl}phosphonate (4e) have shown equal inhibition against the α-amylase enzyme. Compounds diethyl{[(6‐{[(diethoxyphosphoryl)(phenyl)methyl]amino}‐10,10‐dioxo‐9H‐10λ6‐thioxanthen‐3‐yl)-amino](phenyl)methyl}phosphonate (4a), diethyl[(2H‐1,3‐benzodioxol‐5‐yl)[(6‐{[(2H‐1,3‐benzodioxol‐5‐yl)(diethoxyphosphoryl)methyl]amino}‐10,10‐dioxo‐9H‐10λ6‐thioxanthen‐3‐yl)amino]methyl]phosphonate (4h), and diethyl [(anthracen-9-yl)[(6-{[(anthracen-9-yl)(diethoxyphosphoryl)methyl]amino}-10,10-dioxo-9H-10λ6-thioxanthen-3-yl)amino]-methyl]phosphonate (4i) have shown superior inhibition and diethyl{[(6‐{[(diethoxyphosphoryl)(naphthalen‐1‐yl)methyl]amino}‐10,10‐dioxo‐9H‐10λ6‐thioxanthen‐3‐yl)amino](naphthalen‐1‐yl)methyl}phosphonate (4 g) has shown equal inhibition against the α-glucosidase enzyme. All the remaining compounds displayed modest to good inhibition when compared with the reference drug, Acarbose.

4-Adamantyl-(2-(arylidene)hydrazinyl)thiazoles As Potential Antidiabetic Agents: Experimental and Docking Studies

Aim: To develop an efficient and cost-effective antidiabetic agent. Methods: A simple and convenient Hantzsch synthetic strategy was used to prepare 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles. Results: Fifteen newly established structures of 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles were tested for their α-amylase, antiglycation and antioxidant activities. Almost all tested compounds showed excellent α-amylase inhibition. Compounds 3a and 3j exhibited the highest potency, with IC50 values of 16.34±2.67 and 16.64±1.12μM, respectively. Compounds 3c and 3i exhibited comparable antiglycation potential with the standard, aminoguanidine. The antioxidant potential of compound 3g was found to be excellent, with an IC50 value of 28.19±0.2563μM. The binding interactions of compound 3a (binding energy=-8.833kcal/mol) with human pancreatic α-amylase identified 3a as a potent α-amylase inhibitor. Conclusion: Enrichment of established structures with more electron-donating functionalities may assist/lead to the development of more potent antidiabetic drugs.

Anti diabetic activity of Cynodon dactylon Linn In streptozotocin induced Diabetic Rats and its comparison with some standard flavonoids

The aim of present investigation is to evaluate Antidiabetic activity of hydroalcohol extract of whole plant of cynodon dactylon Linn. In streptozotocin induced diabetic rats. Treatment with Cynodon dactylon hydro alcohol extract at two different dose 200 mg/kg and 400 mg/kg and its comparison with standard drug gilbencLinnide at dose of 5 mg/g and some flavonoids i.e. quercertin, kaempferol and epicatichin each at dose of 100mg/kg for 15 days, after induction of diabetes by streptozotocin 50 mg/kg , caused significant decrease in level of tri glycerides, total cholesterol and significantly increase in level of HDL and body weight compared to disease control group. It is furthermore Cynodon dactylon Linn at dose of 200mg/kg and 400mg/kg shows more significant result than some of standard flavonoids. Thus, whole plant of Cynodon dactylon Linn. may have potential Antidiabetic agent.
 

Synthesis, Antidiabetic Evaluation and Molecular Docking Studies of Thiazolidine-2,4-Dione Analogues

Abstract: Introduction: Diabetes Mellitus is a disorder of metabolism described by high glucose levels. The disorder kills a larger number of individuals consistently than of malignant growth and AIDS combined. Presently available drugs have several drawbacks forcing to withdraw from treatment. The potent side effect i.e., hepatotoxicity and cardiovascular toxicity limits the use of thiazolidine-2,4-dione derivative as safe drugs. Our aim is towards the development of synthetic compounds as potential antidiabetic agents, particularly preparation and screening of new analogues of thiazolidine-2,4-dione (TZD) which are well established as oral insulin sensitizing agents that improve insulin resistance and are agonists of Peroxisome Proliferator Activated Receptor–γ (PPAR-γ). Materials and Methods: Proper substitution at C-5 position of thiazolidine-2,4-dione could produce better and potential antidiabetics with improved pharmacological properties, including toxicity. Our aim of this research work is towards this. Results: A series of C-5 substituted thiazolidine-2,4-dione analogues were synthesized. Structures of these new analogues were confirmed by IR, 1H-NMR and MASS spectroscopy. Among the synthesized compounds, three compounds: 5-(2-pyridinylbenzylidene) thiazolidine-2,4-dione, 5-(3,4-dimethoxybenzylidene) thiazolidine-2,4-dione and 5-(2,3,4-trifluorobenzylidene) thiazolidine-2,4-dione showed significant antidiabetic activity in streptozotocin induced diabetic mice comparable with Pioglitazone drug. The molecular docking studies of these compounds performed using protein target showed amino acid interactions with Leu270, Gln283 and Arg288 similar with that of Rosiglitazone and Pioglitazone. The compounds did not show any toxic effect in mice even at 2000 mg/kg of dose. Therefore, synthesis of modified and better thiazolidine-2,4-dione containing drugs other than the currently available drugs is of importance in antidiabetic drug research. Keywords: Thiazolidine-2,4-dione, Molecular docking, Antidiabetic evaluation, Swiss albino mice.

Synthesis, in vitro α-glucosidase inhibitory activity and molecular dynamics simulation of some new coumarin-fused 4H-pyran derivatives as potential anti-diabetic agents

Some new coumarin-fused 4H-pyran derivatives were synthesized and assessed against yeast α-glucosidase enzyme. All of the synthesized compounds showed significant inhibitory activity towards the enzyme with IC50 values in range of 30.05 ± 0.5–274.3 ± 1.0 μM in comparison with acarbose, as a standard agent (IC50 = 750.0 μM). Among them, 4-(4-(4-bromobenzyloxy)-3-methoxyphenyl)-2-amino -4,5-dihydro-5-oxopyrano[3,2-c]chromene-3-carbonitrile (compound 6e) indicated the most potent inhibitory activity. The kinetic study of the compound 6e revealed that this compound inhibited α-glucosidase in a competitive pattern. Homology modeling was utilized to determine 3D structure of the α-glucoside enzyme. Afterwards, the molecular docking and dynamic simulation studies confirmed successful placement of the compound 6e in the active site of α-glucosidase. Besides, the R- and S- enantiomers of the compound 6e showed significant interactions with the catalytic triad residues (Asp214, Glu276, Asp349). The results of in silico prediction study for ADME also indicated that these coumarin-fused 4H-pyran derivatives have acceptable pharmacokinetic and potential therapeutic benefits for the future treatment of type 2 diabetes mellitus (T2DM).

Chemical constituents isolated from Actinidia polygama and their α-glucosidase inhibitory activity and insulin secretion effect

Actinidia polygama has been used as a traditional medicine for treating various diseases. In the present study, 13 compounds, including three new monoterpenoids (1–3), were isolated from the leaves of A. polygama to investigate the bioactive constituents of the plant. The structures were characterized by analyzing spectroscopic and chiroptical data. These compounds were preliminarily screened for their ability to increase insulin secretion levels after glucose stimulation. Of these, 3-O-coumaroylmaslinic acid (4) and jacoumaric acid (5) showed activity. In further biological studies, these compounds exhibited increased glucose‐stimulated insulin secretion (GSIS) activity without cytotoxicity in rat INS-1 pancreatic β-cells as well as α-glucosidase inhibitory activity. Furthermore, both compounds increased insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), pancreatic and duodenal homeobox-1 (PDX-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression. Hence, these compounds may be developed as potential antidiabetic agents.

Synthesis, in-Silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent

Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski’s rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kg p.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 ± 1.35 compared to the standard Pioglitazone (150.2 ± 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The histopathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione derivatives represent novel anti-diabetic agents with least side effects.

The Effects of the Aqueous, Ethanol and Hexane Extracts of Cnidoscolus aconitifolius Leaf on the Hematological Indices and Liver Histological Status of Streptozotocin-induced Diabetic Rats

The effect of the aqueous, ethanol and hexane extracts of Cnidoscolus aconitifolius (Ca) leaf was examined heamatologically and histologically on Streptozotocin - induced diabetic rats . 50 Wistar rats were purchased but only 40 rats were given a single dose of streptozotocin (STZ) (60mg/kg body weight). 25% of STZ dosed animals died while the survivals were distributed into groups II-V. Group II was untreated while groups III, IV and V were treated to hexane, ethanol and aqueous extract of Ca respectively. Rats that constituted the Control group were selected from the STZ untreated animals but were allowed liberty to rat chows and normal saline. Heamatological parameters evaluated revealed significant (P<0.05) increase in the Hb, PCV, and Total Red Blood Count (TRBC) levels when compared with the diabetic group. Furthermore, the Total White Blood Count (TWBC), platelets, neutrophils and lymphocytes were near normal for the Ca extract treated groups as the control. The liver architecture of the STZ-induced diabetic group from this present result displayed distortion of the lobular pattern of the hepatocytes, with several foci of edema and congestion. These were followed by marked periportal hepatolysis and cast within parenchyma. Furthermore, between the hepatocytes were dilation of sinusoids with increased leucocytic infiltration and fibrosis. The nuclei of most cells revealed clear signs of necrosis and the hepatocytes were swollen with conspicuous cytoplasmic vacuolations. Upon treatment with aqueous, hexan and ethanol extracts of C. aconitifolius, sections of the hepatocytes exhibited moderate congestion and improved hepatic features with the aqueous extract exhibiting more potency than the hexane and ethanol extracts. The anti-oxidative tendency of each solvent extract depicts reduced MDA and increased GSH contrary to the diabetic-induced group alone. Hence from this study, the anti-diabetic rationale of C. aconitifolius was further buttressed revealing aqueous solvent extract of C. aconitifolius as a more potent anti-diabetic agent. Keywords: Cnidoscolus aconitifolius (Ca) , heamatology, liver histopathology, streptozotocin DOI: 10.7176/JNSR/14-4-05 Publication date: March 28 th 2023

Synthetic piperidine-substituted chalcones as potential hits for α-amylase inhibitory and antioxidant activities.

Background: In medicinal chemistry, searching for new therapeutic entities to treat diabetes mellitus is of great concern. The piperidinyl-substituted chalcone scaffold has piqued our interest as a potential antidiabetic agent. Methods: A variety of piperidinyl-substituted chalcones 2-28 were synthesized and tested for α-amylase inhibitory and2,2-diphenyl-1-picrylhydrazyl (DPPH) and2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging activities. Results: Compared with the standard acarbose, all compounds inhibited α-amylase, with IC50 values of 9.86-35.98μM. Docking studies revealed animportant binding interaction with the enzyme's catalytic site. The compounds also demonstrated promising radical-scavenging potential against DPPH and ABTS radicals. Conclusion: This study has identified potential lead candidates for further advanced research searching for antidiabetic agents.

New benzimidazole-oxadiazole derivatives: Synthesis, α-glucosidase, α-amylase activity, and molecular modeling studies as potential antidiabetic agents.

Benzimidazole-1,3,4-oxadiazole derivatives (5a-z) were synthesized and characterized with different spectroscopic techniques such as 1 H NMR, 13 C NMR, and HRMS. The synthesized analogs were examined against α-glucosidase and α-amylase enzymes to determine their antidiabetic potential. Compounds 5g and 5q showed the most activity with 35.04 ± 1.28 and 47.60 ± 2.16 µg/mL when compared with the reference drug acarbose (IC50 = 54.63 ± 1.95 µg/mL). Compounds 5g, 5o, 5s, and 5x were screened against the α-amylase enzyme and were found to show excellent potential, with IC50 values ranging from 22.39 ± 1.40 to 32.07 ± 1.55 µg/mL, when compared with the standard acarbose (IC50 = 46.21 ± 1.49 µg/mL). The antioxidant activities of the effective compounds (5o, 5g, 5s, 5x, and 5q) were evaluated by TAS methods. A molecular docking research study was conducted to identify the active site and explain the functions of the active chemicals. To investigate the most likely binding mode of the substances 5g, 5o, 5q, 5s, and 5x, a molecular dynamics simulation was also carried out.

Discovery and evaluation of biphenyl derivatives of 2-iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity.

This work describes the synthesis of series hydrobromides of N-(4-biphenyl)methyl-N'-dialkylaminoethyl-2-iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi-privileged structures. Compound 7a proved to activate AMP-activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual-target mechanism of action. Using prove of concept in vivo study, we show that dual-targeting compound 7a has a disease-modifying effect in a rat model of type 2 diabetes mellitus via improving insulin sensitivity and lipid metabolism.

(1'S)-1'-Acetoxyeugenol Acetate Enhances Glucose-Stimulated Insulin Secretion.

Alpinia galanga have been widely used as spice or traditional medicine in East Asia, commonly known as Thai ginger. In the present study, seven major phenylpropanoids, (±)-1'-hydoxychavicol acetate (1; HCA), (1'S)-1'-acetoxychavicol acetate (2; ACA), (1'S)-1'-acetoxyeugenol acetate (3; AEA), eugenyl acetate (4), trans-p-coumaraldehyde (5), trans-p-acetoxycinnamyl alcohol (6), and trans-p-coumaryl diacetate (7), were isolated from the 95% EtOH and hot water extracts of the rhizomes of A. galanga by chromatographic method. Phenylpropanoids 1-7 were evaluated for glucose-stimulated insulin secretion (GSIS) effect and α-glucosidase inhibitory activity. Phenylpropanoids 1-4 increase GSIS effect without cytotoxicity in rat INS-1 pancreatic β-cells. In addition, INS-1 cells were treated with AEA (3) to determine a plausible mechanism of β-cell function and insulin secretion through determining the activation of insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, and pancreatic and duodenal homeobox-1 (PDX-1). Upon treatment with AEA (3), INS-1 cells showed an increase in these protein expressions. Meanwhile, AEA (3) exhibited α-glucosidase inhibitory activity. On the basis of the above findings, we suggest AEA (3) as a potential antidiabetic agent.

New Succinimide-Thiazolidinedione Hybrids as Multitarget Antidiabetic Agents: Design, Synthesis, Bioevaluation, and Molecular Modelling Studies.

Diabetes mellitus (DM) is a metabolic disorder majorly arising from the pathophysiology of the pancreas manifested as a decline in the insulin production or the tissue's resistance to the insulin. In this research, we have rationally designed and synthesized new succinimide-thiazolidinedione hybrids for the management of DM. In a multistep reaction, we were able to synthesize five new derivatives (10a-e). All the compounds were new containing a different substitution pattern on the N-atom of the succinimide ring. Initially, all the compounds were tested against the in vitro α-glucosidase, α-amylase, PTP1B, and DPP4 targets. In all of these targets, the compound 10d was observed to be the most potential antidiabetic agent. Based on this, the antidiabetic activity of the compound 10d was further investigated in experimental animals, which overall gave us encouraging results. The molecular docking studies of the compound 10d was also performed against the target enzymes α-glucosidase, α-amylase, PTP1B, and DPP4 using MOE. Overall, we observed that we have explored a new class of compounds as potential antidiabetic agents.

The activation of spliced X-box binding protein 1 by isorhynchophylline therapy improves diabetic encephalopathy.

The primary symptom of diabetic encephalopathy (DE), a kind of central diabetic neuropathy caused by diabetes mellitus (DM), is cognitive impairment. In addition, the tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of X-box binding protein 1 (sXBP1) translocation into the nucleus under high glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of phosphatidylinositol 3-kinase (PI3K) p85α or p85β with XBP1 to restore high glucose impairment. Also, IRN treatment improves high glucose-mediated impairment of insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inactivating activating transcription factor 6 (ATF6) and C/EBP homology protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.

Isolation of a Novel Anti-Diabetic α-Glucosidase Oligo-Peptide Inhibitor from Fermented Rice Bran.

At present, the incidence rate of diabetes is increasing gradually, and inhibiting α-glucosidase is one of the effective methods used to control blood sugar. This study identified new peptides from rice bran fermentation broth and evaluated their inhibitory activity and mechanism against α-glucosidase. Rice bran was fermented with Bacillus subtilis MK15 and the polypeptides of <3 kDa were isolated by ultrafiltration and chromatographic column, and were then subjected to LC-MS/MS mass spectrometry analysis. The results revealed that the oligopeptide GLLGY showed the greatest inhibitory activity in vitro. Docking studies with GLLGY on human α-glucosidase (PDB ID 5NN8) suggested a binding energy of -7.1 kcal/mol. GLLGY acts as a non-competitive inhibitor and forms five hydrogen bonds with Asp282, Ser523, Asp616, and His674 of α-glucosidase. Moreover, it retained its inhibitory activity even in a simulated digestion environment in vitro. The oligopeptide GLLGY could be developed into a potential anti-diabetic agent.

Design, synthesis and bio-evaluation of indolin-2-ones as potential antidiabetic agents.

Background: Diabetes mellitus is a serious global health concern, and this is expected to impact more than 300 million people by 2025. The current study focuses on identifying substituted indolin-2-one-based inhibitors for two indispensable drug targets, α-amylase and α-glucosidase. Methods: The structures of synthetic compounds were confirmed by spectroscopic techniques and evaluated for enzyme inhibition activities. Kinetic and in silico studies were also performed. Results: All compounds exhibited good-to-moderate inhibitory potential. Most importantly, compounds 1, 2, 6, 16 and 17 were identified as potent α-glucosidase inhibitors (IC50=9.15±0.12-13.74±0.12μM). Conclusion: This study identified that these synthetic compounds might serve as potential lead molecules for antidiabetic agents.

Quinazolinone-1,2,3-triazole-acetamide conjugates as potent α-glucosidase inhibitors: synthesis, enzyme inhibition, kinetic analysis, and molecular docking study.

In this study, new hybrids of quinazolinone-1,2,3-triazole-acetamide were designed, synthesized, and screened for their α-glucosidase inhibitory activity. The results obtained from the in vitro screening indicated that all analogs exhibited significant inhibitory activity against α-glucosidase (IC50 values ranging from 4.8-140.2 μM) in comparison to acarbose (IC50 = 750.0 μM). The limited structure-activity relationships suggested the variation in the inhibitory activities of the compounds affected by different substitutions on the aryl moiety. The enzyme kinetic studies of the most potent compound 9c, revealed that it inhibited α-glucosidase in a competitive mode with a K i value of 4.8 μM. In addition, molecular docking studies investigated the structural perturbation and behavior of all derivatives inside the α-glucosidase active site. Next, molecular dynamic simulations of the most potent compound 9c, were performed to study the behavior of the 9c-complex during the time. The results showed that these compounds can be considered as potential antidiabetic agents.

In vitro Anti-inflammatory, Anti-diabetic and Anticancer Properties of Copper Nanoparticles Synthesized by Medicinal Plant Leucas aspera (Willd)

Introduction: The present study focuses on the use of Leucas aspera aqueous extract as a reduction agent for the synthesis of copper nanoparticles (CuNPs). The entire plant is employed in conventional medicine and as an insecticide. Scientific research has been done on the plant's potential as an anti-inflammatory, analgesic, and wound-healing agent. Intoxication by cobra venom also makes use of it. This study was intended to explore the in vitro anti-inflammatory, antidiabetic and anticancer activities of copper nanoparticles. Methods: Protein denaturation and membrane stabilization of human red blood cells (HRBC) were used to assess the in vitro anti-inflammatory activity. The antidiabetic activity of the CuNPs was evaluated by inhibiting both amylase and glucosidase in vitro, whereas anticancer activity against vero and MCF-7 cell line. Results: The Leucas aspera copper nanoparticles (LACuNPs) showed a dose dependent -inflammatory activity. The highest inhibition percentage in protein denaturation is 70.30±1.72% and 67.68±1.41% in HRBC membrane stabilization at 1000µg/ml concentration. In vitro antidiabetic activity exhibited 76.03 ± 1.14 of α-amylase and 71.54 ± 1.55 at α-glucosidase inhibition assay. The in vitro anti-cancer study revealed 50% apoptosis (IC₅₀) of LACuNPs treated vero and MCF7 are displayed as 248.84±0.01 µg/ml and 137.39±1.51, respectively. Conclusion: The results clearly demonstrated the application of biosynthesized LACuNPs as potential anti-inflammatory, anti-diabetic, and anticancer agents in addition to their environmental friendliness.

Pyrazoline scaffold: hit identification to lead synthesis and biological evaluation as antidiabetic agents.

Background: Mining of novel scaffolds as potential DPP-IV inhibitors for future development of potential candidates as antidiabetic agents to address global issues. Methodology: The identified hit KB-10 from a previously reported study was taken as a lead for designing a library of analogues and screened initially based on in silico parameters and docking score. A series of selected (2[4-(1-acetyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenoxy]-1-phenylethanone derivatives were synthesized and evaluated through in vitro studies. Compounds KB-23, KB-22 and KB-06 were found to be as potent, with IC50 values of 0.10 μM, 0.12 μM and 0.35 μM, respectively. They also showed promising antihyperglycemic potential in in vivo studies (oral glucose tolerance tests) in Wistar rats. Conclusion: This work establishes pyrazoline analogues KB-23, KB-22 and KB-06 as promising starting points for the development of potential antidiabetic agents.