3-(((1S,3S)-3-((R)-Hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione: Design and Synthesis of New Stereopure Multi-Target Antidiabetic Agent

The chiral drug candidates have more effective binding affinities for their specific protein or receptor site for the onset of pharmacological action. Achieving all carbon stereopure compounds is not trivial in chemical synthesis. However, with the development of asymmetric organocatalysis, the synthesis of certain vital chiral drug candidates is now possible. In this research, we have synthesized 3-(((1S,3S)-3-((R)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione (S,S,R-5) and have evaluated it potential as multi-target antidiabetic agent. The stereopure compound S,S,R-5 was synthesized with a 99:1 enantiomeric ratio. The synthesized compound gave encouraging results against all in vitro antidiabetic targets, exhibiting IC₅₀ values of 6.28, 4.58, 0.91, and 2.36 in α-glucosidase, α-amylase, PTP1B, and DPPH targets, respectively. The molecular docking shows the binding of the compound in homology models of the respective enzymes. In conclusion, we have synthesized a new chiral molecule (S,S,R-5). The compound proved to be a potential inhibitor of the tested antidiabetic targets. With the observed results and molecular docking, it is evident that S,S,R-5 is a potential multitarget antidiabetic agent. Our study laid the baseline for the animal-based studies of this compound in antidiabetic confirmation.     

α-Glucosidase, α-Amylase and Antioxidant Evaluations of Isolated Bioactives from Wild Strawberry

Diabetes mellitus is a metabolic disorder and is a global challenge to the current medicinal chemists and pharmacologists. This research has been designed to isolate and evaluate antidiabetic bioactives from Fragaria indica. The crude extracts, semi-purified and pure bioactives have been used in all in vitro assays. The in vitro α-glucosidase, α-amylase and DPPH free radical activities have been performed on all plant samples. The initial activities showed that ethyl acetate (Fi.EtAc) was the potent fraction in all the assays. This fraction was initially semi-purified to obtain Fi.EtAc 1–3. Among the semi-purified fractions, Fi.EtAc 2 was dominant, exhibiting potent IC₅₀ values in all the in vitro assays. Based on the potency and availability of materials, Fi.EtAc 2 was subjected to further purification to obtain compounds 1 (2,4-dichloro-6-hydroxy-3,5-dimethoxytoluene) and 2 (2-methyl-6-(4-methylphenyl)-2-hepten-4-one). The two isolated compounds were characterized by mass and NMR analyses. The compounds 1 and 2 showed excellent inhibitions against α-glucosidase (21.45 for 1 and 15.03 for 2 μg/mL), α-amylase (17.65 and 16.56 μg/mL) and DPPH free radicals (7.62 and 14.30 μg/mL). Our study provides baseline research for the antidiabetic bioactives exploration from Fragaria indica. The bioactive compounds can be evaluated in animals-based antidiabetic activity in future.     

Thiazolidinedione Derivatives: In Silico,In Vitro,In Vivo,Antioxidant and Anti-Diabetic Evaluation

This work aimed to synthesize a new antihyperglycemic thiazolidinedione based on the spectral data. The DFT\B3LYP\6-311G** level of theory was used to investigate the frontier molecular orbitals (FMOs), chemical reactivity and map the molecular electrostatic potentials (MEPs) to explain how the synthesized compounds interacted with the receptor. The molecular docking simulations into the active sites of PPAR-γ and α-amylase were performed. The in vitro potency of these compounds via α-amylase and radical scavenging were evaluated. The data revealed that compounds (4–6) have higher potency than the reference drugs. The anti-diabetic and anti-hyperlipidemic activities for thiazolidine-2,4-dione have been investigated in vivo using the alloxan-induced diabetic rat model along with the 30 days of treatment protocol. The investigated compounds didn’t show obvious reduction of blood glucose during pre-treatments compared to diabetic control, while after 30 days of treatments, the blood glucose level was lower than that of the diabetic control. Compounds (4–7) were able to regulate hyperlipidemia levels (cholesterol, triglyceride, high-density lipoproteins and low- and very-low-density lipoproteins) to nearly normal value at the 30th day.     

Binding Studies of Caffeic and p-Coumaric Acid with α-Amylase: Multispectroscopic and Computational Approaches Deciphering the Effect on Advanced Glycation End Products (AGEs)

Alpha-amylase (α-amylase) is a key player in the management of diabetes and its related complications. This study was intended to have an insight into the binding of caffeic acid and coumaric acid with α-amylase and analyze the effect of these compounds on the formation of advanced glycation end-products (AGEs). Fluorescence quenching studies suggested that both the compounds showed an appreciable binding affinity towards α-amylase. The evaluation of thermodynamic parameters (ΔH and ΔS) suggested that the α-amylase-caffeic/coumaric acid complex formation is driven by van der Waals force and hydrogen bonding, and thus complexation process is seemingly specific. Moreover, glycation and oxidation studies were also performed to explore the multitarget to manage diabetes complications. Caffeic and coumaric acid both inhibited fructosamine content and AGE fluorescence, suggesting their role in the inhibition of early and advanced glycation end-products (AGEs). However, the glycation inhibitory potential of caffeic acid was more in comparison to p-coumaric acid. This high antiglycative potential can be attributed to its additional –OH group and high antioxidant activity. There was a significant recovery of 84.5% in free thiol groups in the presence of caffeic acid, while coumaric attenuated the slow recovery of 29.4% of thiol groups. In vitro studies were further entrenched by in silico studies. Molecular docking studies revealed that caffeic acid formed six hydrogen bonds (Trp 59, Gln 63, Arg 195, Arg 195, Asp 197 and Asp 197) while coumaric acid formed four H-bonds with Trp 59, Gln 63, Arg 195 and Asp 300. Our studies highlighted the role of hydrogen bonding, and the ligands such as caffeic or coumaric acid could be exploited to design antidiabetic drugs.     

Synthesis,Antibacterial, and Antioxidant Evaluation of Novel Series of Condensed Thiazoloquinazoline with Pyrido,Pyrano, and Benzol Moieties as Five- and Six-Membered Heterocycle Derivatives

A novel synthesis of thiazolo[2,3-b]quinazolines 4(a–e), pyrido[2′,3′:4,5]thiazolo[2,3-b]quinazolines {5(a–e), 6(a–e), and 7(a–e)}, pyrano[2′,3′:4,5]thiazolo[2,3-b]quinazolines 8(a–e), and benzo[4,5]thiazolo[2,3-b]quinazoloine9(a–e) derivatives starting from 2-(Bis-methylsulfanyl-methylene)-5,5-dimethyl-cyclohexane-1,3-dione 2 as efficient α,α dioxoketen dithioacetal is reported and the synthetic approaches of these types of compounds will provide an innovative molecular framework to the designing of new active heterocyclic compounds. In our study, we also present optimization of the synthetic method along with a biological evaluation of these newly synthesized compounds as antioxidants and antibacterial agents against the bacterial strains, like S. aureus, E. coli, and P. aeruginosa. Among all the evaluated compounds, it was found that some showed significant antioxidant activity at 10 μg/mL while the others exhibited better antibacterial activity at 100 μg/mL. The results of this study showed that compound 6(c) possessed remarkable antibacterial activity, whereas compound 9(c) exhibited the highest efficacy as an antioxidant. The structures of the new synthetic compounds were elucidated by elemental analysis, IR, ¹H-NMR, and ¹³C-NMR.     

Identification of Influenza PAN Endonuclease Inhibitors via 3D-QSAR Modeling and Docking-Based Virtual Screening

Structural and biochemical studies elucidate that PA_N may contribute to the host protein shutdown observed during influenza A infection. Thus, inhibition of the endonuclease activity of viral RdRP is an attractive approach for novel antiviral therapy. In order to envisage structurally diverse novel compounds with better efficacy as PA_N endonuclease inhibitors, a ligand-based-pharmacophore model was developed using 3D-QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery Studio. As the training set, 25 compounds were taken to generate a significant pharmacophore model. The selected pharmacophore Hypo1 was further validated by 12 compounds in the test set and was used as a query model for further screening of 1916 compounds containing 71 HIV-1 integrase inhibitors, 37 antibacterial inhibitors, 131 antiviral inhibitors and other 1677 approved drugs by the FDA. Then, six compounds (Hit01–Hit06) with estimated activity values less than 10 μM were subjected to ADMET study and toxicity assessment. Only one potential inhibitory ‘hit’ molecule (Hit01, raltegravir’s derivative) was further scrutinized by molecular docking analysis on the active site of PA_N endonuclease (PDB ID: 6E6W). Hit01 was utilized for designing novel potential PA_N endonuclease inhibitors through lead optimization, and then compounds were screened by pharmacophore Hypo1 and docking studies. Six raltegravir’s derivatives with significant estimated activity values and docking scores were obtained. Further, these results certainly do not confirm or indicate the seven compounds (Hit01, Hit07, Hit08, Hit09, Hit10, Hit11 and Hit12) have antiviral activity, and extensive wet-laboratory experimentation is needed to transmute these compounds into clinical drugs.     

Identification of Antidiabetic Compounds from the Aqueous Extract of Sclerocarya birrea Leaves

Diabetes, a prevalent metabolic condition with a wide range of complications, is fast becoming a global health crisis. Herbal medicine and enhanced extracts are some of the therapeutic options used in the management of diabetes mellitus. The plant-derived molecules and their suitable structure modification have given many leads or drugs to the world such as metformin used as an antidiabetic drug. The stem extract of Sclerocarya birrea has been reported as a potent antidiabetic (glucose uptake) agent. However, the bioactive compounds have not been reported from S. birrea for treatment of diabetes. In this study, the spray-dried aqueous leaf extracts of S. birrea were investigated as an antidiabetic agent using a 2-deoxy-glucose (2DG) technique showing good stimulatory effect on glucose uptake in differentiated C2C12 myocytes with % 2DG uptake ranging from 110–180% that was comparable to the positive control insulin. Three compounds were isolated and identified using bioassay-guided fractionation of the spray-dried aqueous extract of S. birrea leaves: myricetin (1), myricetin-3-O-β-D-glucuronide (2) and quercetin-3-O-β-D-glucuronide (3). Their chemical structures were determined using NMR and mass spectrometric analyses, as well as a comparison of experimentally obtained data to those reported in the literature. The isolated compounds (1–3) were studied for their stimulatory actions on glucose uptake in differentiated C2C12 myocytes. The three compounds (1, 2 and 3) showed stimulatory effects on the uptake of 2DG in C2C12 myocytes with % 2DG uptake ranging from 43.9–109.1% that was better compared to the positive control insulin. Additionally, this is the first report of the flavonoid glycosides (myricetin-3-O-β-D-glucuronide) for antidiabetic activity and they are the main bioactive compound in the extract responsible for the antidiabetic activity. This result suggests that the S. birrea leaves have the potential to be developed for treatment of diabetes.     

Acylhydrazones and Their Biological Activity: A Review

Due to the structure of acylhydrazones both by the pharmacophore –CO–NH–N= group and by the different substituents present in the molecules of compounds of this class, various pharmacological activities were reported, including antitumor, antimicrobial, antiviral, antiparasitic, anti-inflammatory, immunomodulatory, antiedematous, antiglaucomatous, antidiabetic, antioxidant, and actions on the central nervous system and on the cardiovascular system. This fragment is found in the structure of several drugs used in the therapy of some diseases that are at the top of public health problems, like microbial infections and cardiovascular diseases. Moreover, the acylhydrazone moiety is present in the structure of some compounds with possible applications in the treatment of other different pathologies, such as schizophrenia, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Considering these aspects, we consider that a study of the literature data regarding the structural and biological properties of these compounds is useful.     

Pharmacophore-driven identification of PPARγ agonists from natural sources

In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.     

A Multitarget Approach to Evaluate the Efficacy of Aquilaria sinensis Flower Extract against Metabolic Syndrome

Aquilaria sinensis (Lour.) Spreng is known for its resinous secretion (agarwood), often secreted in defense against injuries. We investigated the effects of A. sinensis flower extract (AF) on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake, and lipid accumulation (adipogenesis). Activation of PPARα, PPARγ and LXR was determined in hepatic (HepG2) cells by reporter gene assays. Glucose uptake was determined in differentiated muscle (C2C12) cells using 2-NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose). Adipogenesis was determined in adipocytes (3T3-L1 cells) by Oil red O staining. At a concentration of 50 µg/mL, AF caused 12.2-fold activation of PPARα and 5.7-fold activation of PPARγ, while the activation of LXR was only 1.7-fold. AF inhibited (28%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (32.8%) in muscle cells at 50 μg/mL. It was concluded that AF acted as a PPARα/γ dual agonist without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. This is the first report to reveal the PPARα/γ dual agonistic action and glucose uptake enhancing property of AF along with its antiadipogenic effect, indicating its potential in ameliorating the symptoms of metabolic syndrome.     

Optimization of Two Eco-Friendly Extractions of Black Medick (Medicago lupulina L.) Phenols and Their Antioxidant,Cosmeceutical, α-Glucosidase and α-Amylase Inhibitory Properties

Medicago lupulina is an ancient edible plant from the Fabaceae family. In this work, two eco-friendly methods for extraction of bioactive phenolics from M. lupulina were developed using mixtures of water with two non-toxic, skin- and environmentally-friendly polyol solvents: glycerol and polypropylene glycol. Ultrasound-assisted extractions were optimized using a Box–Behnken design. The independent variables were the concentration of organic solvent in water (X₁), extraction temperature (X₂) and time (X₃), while the response was phenolic content. The optimum conditions for extraction of polyphenols were (X₁, X₂, X₃): (45%, 70 °C, 60 min) and (10%, 80 °C, 60 min) for glycerol and polypropylene glycol extraction, respectively. The extracts prepared at optimum conditions were rich in phenolic compounds, mainly derivatives of apigenin, kaempferol, luteolin, quercetin, caffeic and ferulic acid, as well as coumestrol. Their cosmeceutical and antidiabetic activity was tested. Both extracts demonstrated notable antioxidant, anti-lipoxygenase and anti-α-amylase activity. In addition to those activities, the glycerol extract efficiently inhibited protein coagulation, elastase and α-glucosidase activity. Glycerol present in the extract displayed enzyme-inhibiting activity in several assays and supported the action of the bioactive constituents. Thus, the optimized glycerol extract is a desirable candidate for direct incorporation in antidiabetic food supplements and cosmeceutical products.     

Hydroethanolic Extract of Urtica dioica L. (Stinging Nettle) Leaves as Disaccharidase Inhibitor and Glucose Transport in Caco-2 Hinderer

Herbal treatment for diabetes mellitus is widely used. The pharmacological activity is thought to be due to the phenolic compounds found in the plant leaves. The present study aims to investigate the phytochemical composition of Urtica dioica (UD) hydroethanolic extract and to screen its antidiabetic activity by disaccharidase hindering and glucose transport in Caco-2 cells. The results have shown that a total of 13 phenolic compounds in this work, viz. caffeic and coumaric acid esters (1, 2, 4–7, 10), ferulic derivative (3), and flavonoid glycosides (8, 9, 11–13), were identified using HPLC-DAD-ESI/MS². The most abundant phenolic compounds were 8 (rutin) followed by 6 (caffeoylquinic acid III). Less predominant compounds were 4 (caffeoylquinic acid II) and 11 (kaempferol-O-rutinoside). The UD hydroethanolic extract showed 56%, 45%, and 28% (1.0 mg/mL) inhibition level for maltase, sucrase, and lactase, respectively. On the other hand, glucose transport was 1.48 times less at 1.0 mg/mL UD extract compared with the control containing no UD extract. The results confirmed that U. dioica is a potential antidiabetic herb having both anti-disaccharidase and glucose transport inhibitory properties, which explained the use of UD in traditional medicine.     

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC₅₀ = 0.01–40.50 μM) and one normal MRC5 (IC₅₀ = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC₅₀ = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G₂/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.     

An Insight into All Tested Small Molecules against Fusarium oxysporum f. sp. Albedinis: A Comparative Review

Bayoud disease affects date palms in North Africa and the Middle East, and many researchers have used various methods to fight it. One of those methods is the chemical use of synthetic compounds, which raises questions centred around the compounds and common features used to prepare targeted molecules. In this review, 100 compounds of tested small molecules, collected from 2002 to 2022 in Web of Sciences, were divided into ten different classes against the main cause of Bayoud disease pathogen Fusarium oxysporum f. sp. albedinis (F.o.a.) with structure–activity relationship (SAR) interpretations for pharmacophore site predictions as (δ⁻···δ⁻), where 12 compounds are the most efficient (one compound from each group). The compounds, i.e., (Z)-1-(1.5-Dimethyl-1H-pyrazole-3-yl)-3-hydroxy but-2-en-1-one 7, (Z)-3-(phenyl)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-3-hydroxyprop-2-en-1-one 23, (Z)-1-(1,5-Dimethyl-1H-pyrazole-3-yl)-3-hydroxy-3-(pyridine-2-yl)prop-2-en-1-one 29, and 2,3-bis-[(2-hydroxy-2-phenyl)ethenyl]-6-nitro-quinoxaline 61, have antifungal pharmacophore sites (δ⁻···δ⁻) in common in N1---O4, whereas other compounds have only one δ⁻ pharmacophore site pushed by the donor effect of the substituents on the phenyl rings. This specificity interferes in the biological activity against F.o.a. Further understanding of mechanistic drug–target interactions on this subject is currently underway.     

Encapsulation Preserves Antioxidant and Antidiabetic Activities of Cactus Acid Fruit Bioactive Compounds under Simulated Digestion Conditions

Cactus acid fruit (Xoconostle) has been studied due its content of bioactive compounds. Traditional Mexican medicine attributes hypoglycemic, hypocholesterolemic, anti-inflammatory, antiulcerogenic and immunostimulant properties among others. The bioactive compounds contained in xoconostle have shown their ability to inhibit digestive enzymes such as α-amylase and α-glucosidase. Unfortunately, polyphenols and antioxidants in general are molecules susceptible to degradation due to storage conditions, (temperature, oxygen and light) or the gastrointestinal tract, which limits its activity and compromises its potential beneficial effect on health. The objectives of this work were to evaluate the stability, antioxidant and antidiabetic activity of encapsulated extract of xoconostle within double emulsions (water-in-oil-in-water) during storage conditions and simulated digestion. Total phenols, flavonoids, betalains, antioxidant activity, α-amylase and α-glucosidase inhibition were measured before and after the preparation of double emulsions and during the simulation of digestion. The ED40% (treatment with 40% of xoconostle extract) treatment showed the highest percentage of inhibition of α-glucosidase in all phases of digestion. The inhibitory activity of α-amylase and α-glucosidase related to antidiabetic activity was higher in microencapsulated extracts than the non-encapsulated extracts. These results confirm the viability of encapsulation systems based on double emulsions to encapsulate and protect natural antidiabetic compounds.     

6-Formyl Umbelliferone,a Furanocoumarin from Angelica decursiva L., Inhibits Key Diabetes-Related Enzymes and Advanced Glycation End-Product Formation

Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC₅₀ = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 μM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU’s antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8–100 μM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications.