Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks,Hirshfeld Surface Analysis,In Silico 11β-HSD1 Molecular Docking and ADMET Prediction

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1–3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P2₁/c, P2₁ and P2₁/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1–3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1–3 were determined using in silico techniques. Molecular docking of the compounds into the 11β-HSD1 active site showed comparable binding affinity scores (−7.50 to −8.92 kcal/mol) to the 11β-HSD1 co-crystallized ligand 4YQ (−8.48 kcal/mol, 11β-HSD1 IC₅₀ = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.     

A Novel N-Tert-Butyl Derivatives of Pseudothiohydantoin as Potential Target in Anti-Cancer Therapy

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of glucocorticosteroids, may contribute to the development and implementation of new therapeutic options in the treatment process. Our research focuses on understanding the role of 11β-HSD1 and 11β-HSD2 as factors involved in the differentiation and proliferation of neoplastic cells. In this work, we obtained the 9 novel N-tert-butyl substituted 2-aminothiazol-4(5H)-one (pseudothiohydantoin) derivatives, differing in the substituents at C-5 of the thiazole ring. The inhibitory activity and selectivity of the obtained derivatives in relation to two isoforms of 11β-HSD were evaluated. The highest inhibitory activity for 11β-HSD1 showed compound 3h, containing the cyclohexane substituent at the 5-position of the thiazole ring in the spiro system (82.5% at a conc. 10 µM). On the other hand, the derivative 3f with the phenyl substituent at C-5 showed the highest inhibition of 11β-HSD2 (53.57% at a conc. of 10 µM). A low selectivity in the inhibition of 11β-HSD2 was observed but, unlike 18β-glycyrrhetinic acid, these compounds were found to inhibit the activity of 11β-HSD2 to a greater extent than 11β-HSD1, which makes them attractive for further research on their anti-cancer activity.     

Substituted Aryl Benzylamines as Potent and Selective Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 3

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC₅₀ 17β-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC₅₀ values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC₅₀ of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC₅₀ of 74 nM. Racemic C-allyl derivative 26 (IC₅₀ of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC₅₀ of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.     

GC/MS Analysis of Essential Oil and Enzyme Inhibitory Activities of Syzygium cumini (Pamposia) Grown in Egypt: Chemical Characterization and Molecular Docking Studies

Syzygium cumini (Pomposia) is a well-known aromatic plant belonging to the family Myrtaceae, and has been reported for its various traditional and pharmacological potentials, such as its antioxidant, antimicrobial, anti-inflammatory, and antidiarrheal properties. The chemical composition of the leaf essential oil via gas chromatography–mass spectrometry (GC/MS) analysis revealed the identification of fifty-three compounds representing about 91.22% of the total oil. The identified oil was predominated by α-pinene (21.09%), followed by β-(E)-ocimene (11.80%), D-limonene (8.08%), β-pinene (7.33%), and α-terpineol (5.38%). The tested oil revealed a moderate cytotoxic effect against human liver cancer cells (HepG2) with an IC₅₀ value of 38.15 ± 2.09 µg/mL. In addition, it effectively inhibited acetylcholinesterase with an IC₅₀ value of 32.9 ± 2.1 µg/mL. Furthermore, it showed inhibitory properties against α-amylase and α-glucosidase with IC₅₀ values of 57.80 ± 3.30 and 274.03 ± 12.37 µg/mL, respectively. The molecular docking studies revealed that (E)-β-caryophyllene, one of the major compounds, achieved the best docking scores of −6.75, −5.61, and −7.75 for acetylcholinesterase, α-amylase, and α-glucosidase, respectively. Thus, it is concluded that S. cumini oil should be considered as a food supplement for the elderly to enhance memory performance and for diabetic patients to control blood glucose.     

Antioxidant,Hypoglycemic and Molecular Docking Studies of Methanolic Extract,Fractions and Isolated Compounds from Aerial Parts of Cymbopogon citratus (DC.) Stapf

Traditionally, Cymbopogon citratus is used to treat a variety of ailments, including cough, indigestion, fever, and diabetes. The previous chemical and bioactive research on C. citratus mainly focused on its volatile oil. In this study, 20 non-volatile known compounds were isolated from the dried aerial part of C. citratus, and their structures were elucidated by MS, NMR spectroscopy, and comparison with the published spectroscopic data. Among them, 16 compounds were reported for the first time from this plant. The screening results for antioxidant and α-glucosidase inhibitory activities indicated that compounds caffeic acid (5), 1-O-p-coumaroyl-3-O-caffeoylglycerol (8), 1,3-O-dicaffeoylglycerol (9) and luteolin-7-O-β-D-glucopyranoside (12) had potent antioxidant capacities, with IC₅₀ values from 7.28 to 14.81 μM, 1.70 to 2.15 mol Trolox/mol and 1.31 to 2.42 mol Trolox/mol for DPPH, ABTS, and FRAP, respectively. Meanwhile, compounds 8 and 9 also exhibited significant inhibitory activities against α-glucosidase, with IC₅₀ values of 11.45 ± 1.82 μM and 5.46 ± 0.25 μM, respectively, which were reported for the first time for their α-glucosidase inhibitory activities. The molecular docking result provided a molecular comprehension of the interaction between compounds (8 and 9) and α-glucosidase. The significant antioxidant and α-glucosidase inhibitory activities of compounds 8 and 9 suggested that they could be developed into antidiabetic drugs because of their potential regulatory roles on oxidative stress and digestive enzyme.     

X-ray Structures and Computational Studies of Two Bioactive 2-(Adamantane-1-carbonyl)-N-substituted Hydrazine-1-carbothioamides

Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP–Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N–H···S, N–H···O, C–H···S, C–H···O, H–H bonding and C–H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N–H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds.     

Trifluoromethylated Flavonoid-Based Isoxazoles as Antidiabetic and Anti-Obesity Agents: Synthesis,In Vitro α-Amylase Inhibitory Activity,Molecular Docking and Structure–Activity Relationship Analysis

Diabetes mellitus is a major health problem globally. The management of carbohydrate digestion provides an alternative treatment. Flavonoids constitute the largest group of polyphenolic compounds, produced by plants widely consumed as food and/or used for therapeutic purposes. As such, isoxazoles have attracted the attention of medicinal chemists by dint of their considerable bioactivity. Thus, the main goal of this work was to discover new hybrid molecules with properties of both flavonoids and isoxazoles in order to control carbohydrate digestion. Moreover, the trifluoromethyl group is a key entity in drug development, due to its strong lipophilicity and metabolic stability. Therefore, the present work describes the condensation of a previously synthesized trifluoromethylated flavonol with different aryl nitrile oxides, affording 13 hybrid molecules indicated as trifluoromethylated flavonoid-based isoxazoles. The structures of the obtained compounds were deduced from by ¹H NMR, ¹³C NMR, and HRMS analysis. The 15 newly synthesized compounds inhibited the activity of α-amylase with an efficacy ranging from 64.5 ± 0.7% to 94.7 ± 1.2% at a concentration of 50 μM, and with IC₅₀ values of 12.6 ± 0.2 μM–27.6 ± 1.1 μM. The most effective compounds in terms of efficacy and potency were 3b, 3h, 3j, and 3m. Among the new trifluoromethylated flavonoid-based isoxazoles, the compound 3b was the most effective inhibitor of α-amylase activity (PI = 94.7 ± 1.2% at 50 μM), with a potency (IC₅₀ = 12.6 ± 0.2 μM) similar to that of the positive control acarbose (IC₅₀ = 12.4 ± 0.1 μM). The study of the structure–activity relationship based on the molecular docking analysis showed a low binding energy, a correct mode of interaction in the active pocket of the target enzyme, and an ability to interact with the key residues of glycosidic cleavage (GLU-230 and ASP-206), explaining the inhibitory effects of α-amylase established by several derivatives.     

Discovery of Amide-Functionalized Benzimidazolium Salts as Potent α-Glucosidase Inhibitors

α-Glucosidase inhibitors (AGIs) are used as medicines for the treatment of diabetes mellitus. The α-Glucosidase enzyme is present in the small intestine and is responsible for the breakdown of carbohydrates into sugars. The process results in an increase in blood sugar levels. AGIs slow down the digestion of carbohydrates that is helpful in controlling the sugar levels in the blood after meals. Among heterocyclic compounds, benzimidazole moiety is recognized as a potent bioactive scaffold for its wide range of biologically active derivatives. The aim of this study is to explore the α-glucosidase inhibition ability of benzimidazolium salts. In this study, two novel series of benzimidazolium salts, i.e., 1-benzyl-3-{2-(substituted) amino-2-oxoethyl}-1H-benzo[d]imidazol-3-ium bromide 9a–m and 1-benzyl-3-{2-substituted) amino-2-oxoethyl}-2-methyl-1H-benzo[d] imidazol-3-ium bromide 10a–m were screened for their in vitro α-glucosidase inhibitory potential. These compounds were synthesized through a multistep procedure and were characterized by ¹H-NMR, ¹³C-NMR, and EI-MS techniques. Compound 10d was identified as the potent α-glucosidase inhibitor among the series with an IC₅₀ value of 14 ± 0.013 μM, which is 4-fold higher than the standard drug, acarbose. In addition, compounds 10a, 10e, 10h, 10g, 10k, 10l, and 10m also exhibited pronounced potential for α-glucosidase inhibition with IC₅₀ value ranging from 15 ± 0.037 to 32.27 ± 0.050 µM when compared with the reference drug acarbose (IC₅₀ = 58.8 ± 0.12 μM). A molecular docking study was performed to rationalize the binding interactions of potent inhibitors with the active site of the α-glucosidase enzyme.     

α-Glucosidase Inhibitory and Antimicrobial Benzoylphloroglucinols from Garcinia schomburgakiana Fruits: In Vitro and In Silico Studies

α-Glucosidase plays a role in hydrolyzing complex carbohydrates into glucose, which is easily absorbed, causing postprandial hyperglycemia. Inhibition of α-glucosidase is therefore an ideal approach to preventing this condition. A novel polyprenylated benzoylphloroglucinol, which we named schomburgkianone I (1), was isolated from the fruit of Garcinia schomburgkiana, along with an already-reported compound, guttiferone K (2). The structures of the two compounds were determined using NMR and HRESIMS analysis, and comparisons were made with previous studies. Compounds 1 and 2 exhibited potent α-glucosidase inhibition (IC_50s of 21.2 and 34.8 µM, respectively), outperforming the acarbose positive control. Compound 1 produced wide zones of inhibition against Staphylococcus aureus and Enterococcus faecium (of 21 and 20 mm, respectively), compared with the 19 and 20 mm zones of compound 2, at a concentration of 50 µg/mL. The MIC value of compound 1 against S. aureus was 13.32 µM. An in silico molecular docking model suggested that both compounds are potent inhibitors of enzyme α-glucosidase and are therefore leading candidates as therapies for diabetes mellitus.     

Anti-HIV Ermiasolides from Croton megalocarpus

In recent years, elucidation of novel anti-HIV bioactive compounds from natural products is gaining importance rapidly, not only from the research and publications, but also from controlled clinical studies. Here we report three new anti-HIV eudesmane-type sesquiterpenes, 5β-Hydroxy-8α-methoxy eudesm-7(11)-en-12,8-olide (1), 5β,8α-Dihydroxy eudesm-7(11)-en-12,8-olide (2) and 5β-Hydroxy-8H-β-eudesm-7(11)-en-12,8-olide (3). These are trivially named ermiasolide A-C and were isolated from the bark of Croton megalocarpus. 5β-Hydroxy-8α-methoxy eudesm-7(11)-en-12,8-olide (1), showed the highest anti-HIV activity by inhibiting 93% of the viral replication with an IC₅₀ = 0.002 µg/mL. On the other hand, 5β-Hydroxy-8H-β-eudesm-7(11)-en-12,8-olide (3) and 5β,8α-dihydroxy eudesm-7(11)-en-12,8-olide (2), inhibited viral replication by 77.5% at IC₅₀ = 0.04 µg/mL and 69.5% at IC₅₀ = 0.002 µg/mL, respectively. Molecular docking studies showed that the proposed mechanism of action leading to these results is through the inhibition of HIV-protease.     

Investigation of the Anticancer Effect of α-Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect

Breast cancer is a major cause of death in women worldwide. In this study, 60 female rats were classified into 6 groups; negative control, α-aminophosphonates, arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, DMBA, DMBA & α-aminophosphonates, and DMBA & arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. New α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one were synthesized and elucidated by different spectroscopic and elemental analysis. Histopathological examination showed marked proliferation of cancer cells in the DMBA group. Treatment with α-aminophosphonates mainly decreased tumor mass. Bcl2 expression increased in DMBA-administered rats and then declined in the treated groups, mostly with α-aminophosphonates. The level of CA15-3 markedly declined in DMBA groups treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. Gene expression of GST-P, PCNA, PDK, and PIK3CA decreased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, whereas PIK3R1 and BAX increased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. The molecular docking postulated that the investigated compounds can inhibt the Thymidylate synthase TM due to high hydrophobicity charachter.     

Integration of Two-Dimensional Liquid Chromatography-Mass Spectrometry and Molecular Docking to Characterize and Predict Polar Active Compounds in Curcuma kwangsiensis

Curcuma kwangsiensis, one species of Curcumae zedoaria Ros. c, is a commonly used traditional Chinese medicine (TCM) for treating cardiovascular disease, cancer, asthma and inflammation. Polar compounds are abundant in water decoction, which would be responsible for critical pharmacological effects. However, current research on polar compounds in Curcumae zedoaria Ros. c remains scarce. In this study, the polar fraction from Curcuma kwangsiensis was firstly profiled on G protein-coupled receptor 109A (GPR109A), β2-adrenergic receptor (β2-AR), neurotensin receptor (NTSR), muscarinic-3 acetylcholine receptor (M3) and G protein-coupled receptor 35 (GPR35), which were involved in its clinical indications and exhibited excellent β2-AR and GPR109A receptor activities. Then, an offline two-dimensional reversed-phase liquid chromatography (RPLC) coupled with the hydrophilic interaction chromatography (HILIC) method was developed to separate polar compounds. By the combination of a polar-copolymerized XAqua C18 column and an amide-bonded XAmide column, an orthogonality of 47.6% was achieved. As a result of coupling with the mass spectrometry (MS), a four-dimensional data plot was presented in which 373 mass peaks were detected and 22 polar compounds tentatively identified, including the GPR109A agonist niacin. Finally, molecular docking of these 22 identified compounds to β2-AR, M3, GPR35 and GPR109A receptors was performed to predict potential active ingredients, and compound 9 was predicted to have a similar interaction to the β2-AR partial agonist salmeterol. These results were supplementary to the material basis of Curcuma kwangsiensis and facilitated the bioactivity research of polar compounds. The integration of RPLC×HILIC-MS and molecular docking can be a powerful tool for characterizing and predicting polar active components in TCM.     

Multitarget Action of Xanthones from Garcinia mangostana against α-Amylase, α-Glucosidase and Pancreatic Lipase

Digestive enzymes such α-amylase (AA), α-glucosidase (AG) and pancreatic lipase (PL), play an important role in the metabolism of carbohydrates and lipids, being attractive therapeutic targets for the treatment of type 2 diabetes and obesity. Garcinia mangostana is an interesting species because there have been identified xanthones with the potential to inhibit these enzymes. In this study, the multitarget inhibitory potential of xanthones from G. mangostana against AA, AG and PL was assessed. The methodology included the isolation and identification of bioactive xanthones, the synthesis of some derivatives and a molecular docking study. The chemical study allowed the isolation of five xanthones (1–5). Six derivatives (6–11) were synthesized from the major compound, highlighting the proposal of a new solvent-free methodology with microwave irradiation for obtaining aromatic compounds with tetrahydropyran cycle. Compounds with multitarget activity correspond to 2, 4, 5, 6 and 9, highlighting 6 with IC₅₀ values of 33.3 µM on AA, 69.2 µM on AG and 164.4 µM on PL. Enzymatic kinetics and molecular docking studies showed that the bioactive xanthones are mainly competitive inhibitors on AA, mixed inhibitors on AG and non-competitive inhibitors on PL. The molecular coupling study established that the presence of methoxy, hydroxyl and carbonyl groups are important in the activity and interaction of polyfunctional xanthones, highlighting their importance depending on the mode of inhibition.     

Green Extraction of Forsythoside A,Phillyrin and Phillygenol from Forsythia suspensa Leaves Using a β-Cyclodextrin-Assisted Method

In this study, a green process of β-cyclodextrin (β-CD)-assisted extraction of active ingredients from Forsythia suspensa leaves was developed. Firstly, the optimal process of extraction was as follows: the ratio between Forsythia suspensa leaves and β-CD was 3.61:5, the solid–liquid ratio was 1:36.3, the temperature was 75.25 °C and the pH was 3.94. The yields of forsythoside A, phillyrin and phillygenol were 11.80 ± 0.141%, 5.49 ± 0.078% and 0.319 ± 0.004%, respectively. Then, the structure characteristics of the β-CD-assisted extract of Forsythia suspensa leaves (FSE-β-CD) were analyzed using powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and molecular docking to demonstrate that the natural active products from Forsythia suspensa leaves had significant interactions with the β-CD. Additionally, the loss of forsythoside A from aqueous FSE-CD at 80 °C was only 12%, compared with Forsythia suspensa leaf extract (FSE) which decreased by 13%. In addition, the aqueous solubility of FSE-CD was significantly increased to 70.2 g/L. The EC₅₀ for scavenging DPPH and ABTS radicals decreased to 28.98 ug/mL and 25.54 ug/mL, respectively. The results showed that the β-CD-assisted extraction process would be a promising technology for bioactive compounds extracted from plants.     

Inhibitory Activity and Mechanism Investigation of Hypericin as a Novel α-Glucosidase Inhibitor

α-glucosidase is a major enzyme that is involved in starch digestion and type 2 diabetes mellitus. In this study, the inhibition of hypericin by α-glucosidase and its mechanism were firstly investigated using enzyme kinetics analysis, real-time interaction analysis between hypericin and α-glucosidase by surface plasmon resonance (SPR), and molecular docking simulation. The results showed that hypericin was a high potential reversible and competitive α-glucosidase inhibitor, with a maximum half inhibitory concentration (IC₅₀) of 4.66 ± 0.27 mg/L. The binding affinities of hypericin with α-glucosidase were assessed using an SPR detection system, which indicated that these were strong and fast, with balances dissociation constant (KD) values of 6.56 × 10⁻⁵ M and exhibited a slow dissociation reaction. Analysis by molecular docking further revealed that hydrophobic forces are generated by interactions between hypericin and amino acid residues Arg-315 and Tyr-316. In addition, hydrogen bonding occurred between hypericin and α-glucosidase amino acid residues Lys-156, Ser-157, Gly-160, Ser-240, His-280, Asp-242, and Asp-307. The structure and micro-environment of α-glucosidase enzymes were altered, which led to a decrease in α-glucosidase activity. This research identified that hypericin, an anthracene ketone compound, could be a novel α-glucosidase inhibitor and further applied to the development of potential anti-diabetic drugs.     

Multi-Targeted Molecular Docking,Pharmacokinetics, and Drug-Likeness Evaluation of Okra-Derived Ligand Abscisic Acid Targeting Signaling Proteins Involved in the Development of Diabetes

Diabetes mellitus is a global threat affecting millions of people of different age groups. In recent years, the development of naturally derived anti-diabetic agents has gained popularity. Okra is a common vegetable containing important bioactive components such as abscisic acid (ABA). ABA, a phytohormone, has been shown to elicit potent anti-diabetic effects in mouse models. Keeping its anti-diabetic potential in mind, in silico study was performed to explore its role in inhibiting proteins relevant to diabetes mellitus- 11β-hydroxysteroid dehydrogenase (11β-HSD1), aldose reductase, glucokinase, glutamine-fructose-6-phosphate amidotransferase (GFAT), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and Sirtuin family of NAD(+)-dependent protein deacetylases 6 (SIRT6). A comparative study of the ABA-protein docked complex with already known inhibitors of these proteins relevant to diabetes was compared to explore the inhibitory potential. Calculation of molecular binding energy (ΔG), inhibition constant (pKi), and prediction of pharmacokinetics and pharmacodynamics properties were performed. The molecular docking investigation of ABA with 11-HSD1, GFAT, PPAR-gamma, and SIRT6 revealed considerably low binding energy (ΔG from −8.1 to −7.3 Kcal/mol) and predicted inhibition constant (pKi from 6.01 to 5.21 µM). The ADMET study revealed that ABA is a promising drug candidate without any hazardous effect following all current drug-likeness guidelines such as Lipinski, Ghose, Veber, Egan, and Muegge.     

Anti-Inflammatory,Antidiabetic Properties and In Silico Modeling of Cucurbitane-Type Triterpene Glycosides from Fruits of an Indian Cultivar of Momordica charantia L.

Diabetes mellitus is a chronic disease and one of the fastest-growing health challenges of the last decades. Studies have shown that chronic low-grade inflammation and activation of the innate immune system are intimately involved in type 2 diabetes pathogenesis. Momordica charantia L. fruits are used in traditional medicine to manage diabetes. Herein, we report the purification of a new 23-O-β-d-allopyranosyl-5β,19-epoxycucurbitane-6,24-diene triterpene (charantoside XV, 6) along with 25ξ-isopropenylchole-5(6)-ene-3-O-β-d-glucopyranoside (1), karaviloside VI (2), karaviloside VIII (3), momordicoside L (4), momordicoside A (5) and kuguaglycoside C (7) from an Indian cultivar of Momordica charantia. At 50 µM compounds, 2–6 differentially affected the expression of pro-inflammatory markers IL-6, TNF-α, and iNOS, and mitochondrial marker COX-2. Compounds tested for the inhibition of α-amylase and α-glucosidase enzymes at 0.87 mM and 1.33 mM, respectively. Compounds showed similar α-amylase inhibitory activity than acarbose (0.13 mM) of control (68.0–76.6%). Karaviloside VIII (56.5%) was the most active compound in the α-glucosidase assay, followed by karaviloside VI (40.3%), while momordicoside L (23.7%), A (33.5%), and charantoside XV (23.9%) were the least active compounds. To better understand the mode of binding of cucurbitane-triterpenes to these enzymes, in silico docking of the isolated compounds was evaluated with α-amylase and α-glucosidase.     

On the Inhibitability of Natural Products Isolated from Tetradium ruticarpum towards Tyrosine Phosphatase 1B (PTP1B) and α-Glucosidase (3W37): An In Vitro and In Silico Study

Folk experiences suggest natural products in Tetradium ruticarpum can be effective inhibitors towards diabetes-related enzymes. The compounds were experimentally isolated, structurally elucidated, and tested in vitro for their inhibition effects on tyrosine phosphatase 1B (PTP1B) and α-glucosidase (3W37). Density functional theory and molecular docking techniques were utilized as computational methods to predict the stability of the ligands and simulate interaction between the studied inhibitory agents and the targeted proteins. Structural elucidation identifies two natural products: 2-heptyl-1-methylquinolin-4-one (1) and 3-[4-(4-methylhydroxy-2-butenyloxy)-phenyl]-2-propenol (2). In vitro study shows that the compounds (1 and 2) possess high potentiality for the inhibition of PTP1B (IC₅₀ values of 24.3 ± 0.8, and 47.7 ± 1.1 μM) and α-glucosidase (IC₅₀ values of 92.1 ± 0.8, and 167.4 ± 0.4 μM). DS values and the number of interactions obtained from docking simulation highly correlate with the experimental results yielded. Furthermore, in-depth analyses of the structure–activity relationship suggest significant contributions of amino acids Arg254 and Arg676 to the conformational distortion of PTP1B and 3W37 structures overall, thus leading to the deterioration of their enzymatic activity observed in assay-based experiments. This study encourages further investigations either to develop appropriate alternatives for diabetes treatment or to verify the role of amino acids Arg254 and Arg676.     

N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides: Molecular Docking,Synthesis, and Biological Investigation as Anticancer Agents

Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (¹H and ¹³C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC₅₀ µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues.