Search

Fifteen N4-benzyl-5 μm). In the phytotoxicity assay, 11 thiosemicarbazones 5a-d, 5g, 5hsubstituted isatin-3-thiosemicarbazones 5a-o were synthesized and evaluated for their urease and glycation inhibitory potential. Lemna aequinocitalis growth and Artemia salina assays were also done to determine their phytotoxic and toxic effects. All compounds are potent inhibitors of the urease enzyme, displaying inhibition [half maximal inhibitory concentration (IC50) = 1.08 ± 0.12-11.23 ± 0.19 µm] superior to that of the reference inhibitor thiourea (IC50 = 22.3 ± 1.12 μm). Compounds 5c, 5d, 5h, 5j,k are potent antiglycating agents, showing glycation inhibitory activity better than that of the reference inhibitor rutin (IC50 values 209.87 ± 0.37- 231.70 ± 6.71 vs. 294.5 ± 1., 5j-l, 5n,o are active, demonstrating 5-100% growth inhibition of L. aequinocitalis at the highest tested concentrations (1000 or 500 μg/mL). In the brine shrimp (A. salina) lethality bioassay, three derivatives 5b, 5j and 5o are active with median lethal dose (LD50) values of 3.63 × 10-5, 2.90 × 10-5 and 2.31 × 10-4 m, respectively. [ABSTRACT FROM AUTHOR]

α -Glucosidase inhibitors have extensively been exploited for the effective management of type 2 diabetes and associated complications by significantly reducing the postprandial increase in glucose and plasma insulin levels. In this endeavour, we designed and synthesized a new series of coumarinyl iminothiazolidinone hybrid compounds ( 6a‒o ) using a one-pot multi-component approach. The hybrid structures were accessed in good chemical yields. The synthesized compounds were tested for their glucosidase inhibitory efficacy using acarbose as a standard inhibitor (IC 50 = 38.2 ± 0.12 µM). In-vitro analysis of the hybrid molecules identified several potential leads for the development of potent glucosidase inhibitors with IC 50 values in the range of 0.09‒0.92 µM with compound 6g being the most potent drug candidate (IC 50 = 0.09 ± 0.001 µM). Furthermore, compound 6f was identified as the lead inhibitor against maltase-glucoamylase with comparable inhibitory efficacy to acarbose with an IC 50 value of 0.07 ± 0.016 µM. Binding interactions of potent compounds with the key residues in the active site of the glucosidase enzyme were revealed by molecular docking analysis. In summary, these new structural leads based on the hybrid pharmacophores could be developed as potential inhibitors of α -glucosidase for treating postprandial hyperglycemia. [ABSTRACT FROM AUTHOR]

Background: Phytotherapeutics exhibit diverse pharmacological effects that are based on the combined action of a mixture of phytoconstituents. In this study, Prunus domestica gum-loaded, stabilized gold and silver nanoparticles (Au/Ag-NPs) were evaluated for their prospective anticancer, antibacterial, urease-inhibition, anti-inflammatory, and analgesic properties. Methods: Au/Ag-NPs were biosynthesized and characterized with UV-Vis, FTIR, SEM, EDX, and XRD techniques. The effect of gum and metal ion concentration, reaction temperature, and time on the synthetic stability of nanoparticles was studied along with their post-synthetic stability against varying pH and salt concentrations, longterm storage and extremes of temperature. Nanoparticles were tested for anticancer (HeLa cervical cancer cells), antibacterial (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), urease inhibition (jack-bean urease), anti-inflammatory (carrageenan-induced paw edema), and antinociceptive (abdominal constriction response) activities. Results: The nanoparticles were mostly spherical with an average particle size between 7 and 30 nm (Au-NPs) and 5-30 nm (Ag-NPs). Au/Ag-NPs maintained their colloidal stability and nanoscale characteristics against variations in physicochemical factors. Au/Ag-NPs have potent anticancer potential (IC50 = 2.14 ± 0.15 µg/mL and 3.45 ± 0.23 µg/ mL). Au/Ag-NPs selectively suppressed the growth of S. aureus (10.5 ± 0.6 mm, 19.7 ± 0.4 mm), E. coli (10 ± 0.4 mm, 14.4 ± 0.7 mm), and P. aeruginosa (8.2 ± 0.3 mm, 13.1 ± 0.2 mm), as well as showed preferential inhibition against jack-bean urease (19.2 ± 0.86%, 21.5 ± 1.17%). At doses of 40 and 80 mg/kg, Au-NPs significantly ameliorated the increase in paw edema during the 1st h (P < 0.05, P < 0.01) and 2-5 h (P < 0.001) of carrageenan-induced inflammation compared to the 200 and 400 mg/kg doses of P. domestica gum (P < 0.05, P < 0.001). At similar doses, Au-NPs also significantly abolished (P < 0.01) the tonic visceral, chemically-induced nociception, which was comparable to that of P. domestica gum (200 mg/kg; P < 0.05, 400 mg/kg; P < 0.01). [ABSTRACT FROM AUTHOR]

• Investigation of noncovalent interactions in tetrahydrocarbazole-carbonitrile scaffold. • Understanding the role of O H...N, N H...O, C H...π and π...π interactions. • Visualization of NCIs using molecular electrostatic potential. • Unraveling the energetic features of NCIs using QTAIM and NCIPlot methods. • In vitro urease inhibition evaluation revealing a 4-fold strong efficacy. • Binding mode analysis and computation of pharmacokinetic properties. Organic crystals hold a significant importance in pharmaceuticals, biological systems and functional materials. In the present study, a tricyclic aromatic structure, tetrahydrocarbazole (THC), incorporating a nitrile functionality was synthesized via the Fischer indolization of 4-hydroxycyclohexanone with 4-hydrazinobenzonitrile hydrochloride in 70% yield. The detailed description of noncovalent interactions of various types and strengths in the crystal structure of tetrahydrocarbazole-carbonitrile was investigated using a combination of experimental and theoretical methods. The supramolecular assembly of THC involved the extensive network of N H...O and O H...N hydrogen bonds, and weaker π...π and C H...π contacts. The nature of noncovalent interactions was visualized using molecular electrostatic potential whereas QTAIM and NCIPlot methods revealed the energetic features of π-stacking and H-bonding in the supramolecular assemblies of tetrahydrocarbazole-carbonitrile. In vitro evaluation of urease inhibitory potential of target compound revealed a 4-fold strong inhibition (IC 50 = 5.26 ± 0.10 µM) compared to standard drug (thiourea; IC 50 = 22.3 ± 1.06 µM). Finally, molecular docking analysis showed significant interactions of target compound with various active site amino acids of Jack bean urease. Combined QTAIM and NCIplot analyses of an H-bonded trimer (a) and an antiparallel self-assembled dimer (b) of 3 are described. [Display omitted] [ABSTRACT FROM AUTHOR]

A facile and robust microwave-assisted solution phase parallel synthesis protocol was exercised for the development of a 38-member library of N , N ′-disubstituted thiourea analogues ( 1 – 38 ) by using an identical set of conditions. The reaction time for synthesis of N , N ′-disubstituted thiourea analogues was drastically reduced from a reported duration of 8–12 h for conventional methods to only 1.5–2.0 min. All the derivatives ( 1 – 38 ) were characterized by physico-analytical techniques such as elemental analysis in combination with FT-IR, 1 H, 13 C NMR and by single crystal XRD analysis have also been performed. These compounds were screened for their in vitro urease inhibition activities. Majority of compounds exhibited potent urease inhibition activities, however, the most significant activity was found for 16 , with an IC 50 value of 1.23 ± 0.1 μM. Furthermore, the synthesized compounds were screened for their cytotoxic potential against lungs cancer cell lines. Cell culture studies demonstrated significant toxicity of the compounds on the cell lines, and the levels of toxicity were altered in the presence of various side groups. The molecular docking studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the urease enzymes. These compounds have a great potential and significance for further investigations. [ABSTRACT FROM AUTHOR]

Nitrogen-rich heterocycles, particularly quinazolines and quinazolinones, represent a unique class of diversified frameworks displaying a broad spectrum of biological functions. Over the past several years, intensive medicinal chemistry efforts have generated numerous structurally functionalized quinazoline and quinazolinone derivatives. Interest in expanding the biological effects, demonstrated by these motifs, is growing exponentially, as indicated by the large number of publications reporting the easy accessibility of these skeletons in addition to the diverse nature of synthetic as well as biological applications. Therefore, the main focus of the present review is to provide an ample but condensed overview on various synthetic approaches providing access to quinazoline and quinazolinone compounds with multifaceted biological activities. Furthermore, mechanistic insights, synthetic utilization, structure–activity relationships and molecular modeling inputs for the potent derivatives have also been discussed. [ABSTRACT FROM AUTHOR]

• Nitrile pharmacophore is a well-known fragment in various pharmaceuticals. • Crystal engineering of cyclic aminobenzonitriles has been investigated. • Hydrogen bonding and C‒H...π(CN) interactions stabilized the structural topology. • QTAIM/NCIplot computational tool was used to characterize the noncovalent interactions. The essential role of organic crystals in drug development represents a significant research area and remains enduringly topical within the pharmaceutical industry. In the present study, four cyclic aminobenzonitriles 3a-d were prepared through the nucleophilic aromatic substitution reaction of 4-fluorobenzonitrile with various cyclic amines. The synthesized compounds were obtained in moderate to good yields and structurally characterized by FTIR, NMR spectroscopy, mass spectrometry and X-ray crystallography. The crystal packing of these compounds predominantly involves the use of hydrogen bonding interactions (C-H...N, C-H...S, C-H...O) and aromatic contacts (C-H...π(ring & CN), π...π) to govern the complex structural topology. These noncovalent interactions were further evaluated by molecular electrostatic potential (MEP) surface analysis and DFT energy calculations confirming the importance of π-stacking and CH ... π interactions, either involving the arene or the π-system of the cyano groups. These interactions have been further characterized using the QTAIM/NCIplot computational tool. QTAIM and NCIplot analyses of the assembly of compound 3c and the π-π dimer of 3d [Display omitted]. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ellagitannin, gallotannin and anthocyanin derivatives exhibited varying degree of AChE, BChE and BACE1 inhibition. • Enzyme kinetic and docking simulation studies were simultaneously performed. • Amino acid residues on AChE, BChE and BACE1 interacted with functional groups of compounds. • Gallagic acid and castalagin decreased Aβ peptides secretion from neuroblastoma cells. • Gallagic acid and castalagin reduced BACE1 and APPsβ expression levels significantly. Pomegranate (Punica granatum L.) extract has been reported to inhibit cholinesterase and the β-site amyloid precursor protein cleaving enzyme 1 (BACE1); however, most of its constituents' potential inhibition of these enzymes remains unknown. Thus, we investigated the anti-Alzheimer's disease (anti-AD) potential of 16 ellagitannin and gallotannin, and nine anthocyanin derivatives' inhibition of BACE1, AChE, and BChE, and gallagic acid inhibited both the best. Further, a kinetic study identified different modes of inhibition, and a molecular docking simulation revealed that active compounds inhibited these three enzymes with low binding energy through hydrophilic and hydrophobic interactions in the active site cavities. Gallagic acid and castalagin decreased Aβ peptides secretion from neuroblastoma cells that overexpressed human β-amyloid precursor protein significantly by 10 μM. Further, treatment with gallagic acid and castalagin reduced BACE1 and APPsβ expression levels significantly without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Co-incubation of Aβ42 with gallagic acid reduced Aβ42-induced intracellular reactive oxygen species (ROS) production significantly. Our results suggest that pomegranate constituents, specifically gallagic acid, may be useful in developing therapeutic treatment modalities for AD. [ABSTRACT FROM AUTHOR]

A series of N, N, N′-trisubstituted thioureas ( 1-12) and their Ni(II) complexes ( 1a-12a) were synthesized and characterized by multinuclear (H and C) NMR, FT-IR spectroscopy and LC-MS techniques in combination with elemental analysis. The crystal structures of both ligands and Ni(II) chelates of type Ni(L- O, S) were determined by single crystal X-ray diffraction analysis. All the complexes were adopted to have square planar geometry, where the N, N, N′-trisubstituted thioureas showed bidentate mode of coordination at nickel centre through oxygen and sulfur atoms. The synthesized complexes were screened for potential inhibitors of Jack bean urease. Compounds 1a and 3a were observed as most potent inhibitors of urease exhibiting IC values of 1.17 ± 0.12 and 1.19 ± 0.41 µM, respectively. Cytotoxicity assay on lung carcinoma (H-157) and kidney fibroblast (BHK-21) cell showed that compounds were significant anticancer agents. Additionally, the complexes were tested against Leishmania major and found to be potent antileishmanial agents. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate in vitro antioxidant, NO scavenging, and antibacterial activities as well as total phenolic contents of different extracts of flowers of Jasminum humile and roots of Dorema aucheri. The plant extracts showed significant antioxidant activity, having IC50 values comparable to those of references used in each assay and also inhibited accumulation of nitrite in vitro. The plant extracts yielded phenolic contents and showed significant antibacterial activity. The observed antioxidant potential and phenolic contents of the extracts showed that flowers of J. humile and roots of D. aucheri are potential source of natural antioxidants that may help to retard oxidative degradation and microbial growth in food industry. [ABSTRACT FROM AUTHOR]

• Tetrazolyl tryptophol hybrid achieved through a multistep synthetic approach. • Investigation of H-bonding networks and π–stacking interactions. • An insight into intermolecular interactions using Hirshfeld surface analysis. • Crystal voids analysis and intermolecular interaction energy frameworks. • DFT calculations focusing on the H-bonds and π–π interactions. The present study reports the synthesis of a new nitrogen rich hybrid compound namely tetrazolyl tryptophol 6 achieved through a multistep synthetic approach. The structure of the target tetrazole-indole hybrid was established using FTIR, 1H- and 13C NMR, HRMS, and X-ray diffraction data. Investigation of solid state architectures in tetrazolyl tryptophol revealed that an intramolecular N5-H5N...N4 hydrogen bond links the 5-membered ring of the indole to the tetrazole ring. O1-H1O...N3 and N1-H1N...O1 hydrogen bonds and π...π contacts also emerged as crucial contributors in the formation of supramolecular topology of tetrazole-indole hybrid. Numerous centroid to centroid contacts involving the aromatic rings of both the indole ring system and the tetrazole ring link adjacent molecules in an obverse face-to-face fashion. Hirshfeld surface analysis further revealed the prevailing significance of π...π and H-bonding contacts. The mechanical stability of the crystal packing through crystal voids analysis and intermolecular interaction energies were also calculated. Finally, DFT calculations were performed to evaluate the hydrogen bonding and π...π stacking contacts with their rationalization and characterization using MEP surfaces, QTAIM and NCIPlot analysis. Combined QTAIM and NCIplot analyses of an H-bonded trimer (a) and self-assembled dimer (b) of 6 are described. The overlap of the π-clouds as well as a weak C–H ··· N interaction between one CH group of 2-hydroxyethyl substituent and one N-atom of the tetrazole ring contribute to the stabilization of the system. [Display omitted] [ABSTRACT FROM AUTHOR]

The present study reports the successful synthesis and evaluation of a series of indole-picolinamide hybrids as potent inhibitors of bovine carbonic anhydrase II, a promising therapeutic target for the treatment of neurological disorders, osteoporosis, glaucoma, cancer, and obesity. Various multistep synthetic approaches were utilized to access the desired structures having exclusive sites for chemical modifications and diverse spots for biological interactions between the ligand and enzyme. Compound 1a was observed as a potent inhibitor of the bovine CA-II with an IC 50 value of 0.0440 ± 0.009 µM. The inhibition potency was about 22-fold higher than the standard drug acetazolamide (IC 50 = 0.9618 ± 0.180 µM). Several impactful structure-activity relationships were deduced that enlighten the crucial role of substituents as well as the key pharmacophores involved in the inhibition process. Molecular docking tools reinforced the in vitro assay results. The most active compound 1a was also investigated for anticancer potential using sulforhodamine B assay and results showed two-fold efficacy against HeLa cells when compared to standard drug cisplatin (IC 50 = 8.045 ± 3.791 µg/mL and 4.128 ± 1.473 µg/mL, respectively). These findings were also confirmed by flow cytometry and comet tests. Moreover, fluorescence microscopy with DAPI staining revealed apoptosis as a mechanism of cancer cell death. The graphical abstract representing the 3D docked pose, RMSD graph of 1V9E with compound 1a, DAPI staining and genotoxicity assay of the most potent compound [Display omitted] [ABSTRACT FROM AUTHOR]

Figure representing the 2D interactions, RMSF and visual/ investigative modes of the docked pose of compound 1q within the active site of urease. [Display omitted] • Urease-inhibitory activity of a series of sulfamate derivatives is reported. • Ten compounds have shown sub-micromolar IC 50 values. • Compound 1q is the most potent urease inhibitor (IC 50 = 0.062 µM). • Compound 1q is 372-fold more potent urease inhibitor than thiourea. • In silico studies were conducted to explain the binding interactions. The discovery of life-changing medicines continues to be the driving force for the rapid exploration and expansion of chemical space, enabling access to innovative small molecules of medicinal importance. These small molecules remain the backbone for modern drug discovery. In this context, the treatment of ureolytic bacterial infections inspires the identification of potent and effective inhibitors of urease, a promising and highly needed target for H. pylori eradication. The present study explores the evaluation of sulfamate derivatives for the inhibition of urease enzyme. The tested compounds showed remarkable inhibitory effect and high level of potency. Compound 1q emerged as the lead inhibitor with an IC 50 value of 0.062 ± 0.001 µM, ∼360-fold more potent than thiourea (IC 50 = 22.31 ± 0.031 µM). The assessment of various contributing factors towards the inhibition profile allowed for the establishment of diverse structure–activity relationships. Kinetics studies revealed the competitive mode of inhibition of compound 1q while molecular modeling analysis identified various crucial binding interactions with ARG609, ARG439, HIS519, HIS492, HIS593, ALA440, and ALA636 in the active pocket of the enzyme. Finally, the calculated pharmacokinetic properties suggest a promising profile of our potent sulfamate-based urease inhibitors. [ABSTRACT FROM AUTHOR]

The present review summarizes the recent developments in the synthetic methodologies and medicinal applications of phthalazine nucleus. Various challenges associated with the drug design and future opportunities for the scientific community have also been included in the discussion. • New synthetic methods for the synthesis of phthalazine core. • Diverse utility of readily accessible and commercial precursors. • A discussion on the medicinal importance of phthalazines. • Exploration of structure-activity relationship analyses in drug design. • Exchange of bioactive pharmacophores provides a significant boost in potency. Fused diaza-heterocycles constitute the core structure of numerous bioactive natural products and effective therapeutic drugs. Among them, phthalazines have been recognized as remarkable structural leads in medicinal chemistry due to their wide application in pharmaceutical and agrochemical industries. Accessing such challenging pharmaceutical agents/drug candidates with high chemical complexity through synthetically efficient approaches remains an attractive goal in the contemporary medicinal chemistry and drug discovery arena. In this review, we focus on the recent developments in the synthetic routes towards the generation of phthalazine-based active pharmaceutical ingredients and their biological potential against various targets. The general reaction scope of these innovative and easily accessible strategies was emphasized focusing on the functional group tolerance, substrate and coupling partner compatibility/limitation, the choice of catalyst, and product diversification. These processes were also accompanied by the mechanistic insights where deemed appropriate to demonstrate meaningful information. Moreover, the rapid examination of the structure-activity relationship analyses around the phthalazine core enabled by the pharmacophore replacement/integration revealed the generation of robust, efficient, and more selective compounds with pronounced biological effects. A large variety of in silico methods and ADME profiling tools were also employed to provide a global appraisal of the pharmacokinetics profile of diaza-heterocycles. Thus, the discovery of new structural leads offers the promise of improving treatments for various tropical diseases such as tuberculosis, leishmaniasis, malaria, Chagas disease, among many others including various cancers, atherosclerosis, HIV, inflammatory, and cardiovascular diseases. We hope this review would serve as an informative collection of structurally diverse molecules enabling the generation of mature, high-quality, and innovative routes to support the drug discovery endeavors. [ABSTRACT FROM AUTHOR]

• Poncirin strongly inhibit α-glucosidase, PTP1B, RLAR, HRAR, and AGE (IC 50 7.76, 11.91, 3.56, 3.23 µM). • Poncirin stimulates glucose uptake and decrease PTP1B level in insulin resistant C2C12 muscle cells. • Poncirin activate GLUT4 via IRS-1/PI3K/Akt and GSK-3β signaling pathway. • Poncirin suppresses glycation-induced protein oxidation and formation of amyloid cross-β structures. • Poncirin might be useful for the treatment of diabetes and its complications. Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC 50 = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highest affinity for the mixed and competitive type of inhibitors of poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5–50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and β-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications. [ABSTRACT FROM AUTHOR]

The urease enzyme is recognized as a valuable therapeutic agent for treating the virulent Helicobacter pylori bacterium because of its pivotal role in aiding the colonization and growth of the bacterium within the gastric mucosa. In order to control the harmful consequences of bacterial infections, urease inhibition presents itself as a promising and effective approach. The current research aimed to synthesize pyridylpiperazine-based carbodithioate derivatives 5a-5n and 7a-7n that could serve as potential drug candidates for preventing bacterial infections through urease inhibition. The synthesized carbodithioate derivatives 5a-5n and 7a-7n were explored to assess their ability to inhibit the urease enzyme after their structural explication by gas chromatography-mass spectrometry (GC-MS). In the in vitro evaluation with thiourea as a standard drug, it was observed that all the synthesized compounds exhibited significant inhibitory activity compared to the reference drug. Among the compounds tested, 5j (bearing an o-tolyl moiety) emerged as the most effective inhibitor, displaying strong urease inhibition with an IC50 value of 5.16 ± 2.68 pM. This IC50 value is notably lower than that of thiourea (23 ± 0.03 pM), indicating the significantly most potent potential of inhibition. In molecular docking of 5j within the active site of urease, numerous noteworthy interactions were identified. [ABSTRACT FROM AUTHOR]

In diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a–g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a–g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall, the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2. The binding site analysis of potent compounds revealed similar interactions as were found by cognate ligands within the active sites of enzymes. [ABSTRACT FROM AUTHOR]

Abstract We report the synthesis and biological evaluation of two new series of 2-amino-6-benzyl-4-phenyl-4,6-dihydrobenzo[ c ]pyrano[2,3- e ][1,2]thiazine-3‑carbonitrile 5,5-dioxides and 2-amino-6-methyl-4-phenyl-4,6-dihydrobenzo[ c ]pyrano[2,3- e ][1,2]thiazine-3‑carbonitrile 5,5-dioxides. The synthetic methodology involves a multistep reaction starting with methyl anthranilate which was coupled with methane sulfonyl chloride. The product of the reaction was subjected to N -benzylation and N -methylation reactions followed by ring closure with sodium hydride resulting in the formation of respective 2,1-benzothiazine 2,2-dioxides. These 2,1-benzothiazine precursors were subjected to multicomponent reaction with malononitrile and substituted benzaldehydes for the synthesis of two new series of pyranobenzothiazines (6a – r and 7a – r). The synthesized compounds were screened as selective inhibitors of monoamine oxidase A and monoamine oxidase B. The in vitro results suggested that compound 6d and 7q are the selective inhibitors of monoamine oxidase A, however, the selective and potent inhibitors of monoamine oxidase B included compounds 6h and 7r. Moreover, some dual inhibitors were noticed like 7l having more inhibitory activity towards both the isozymes. Moreover, the binding modes of the selective and potent inhibitors of monoamine oxidase A and B were investigated by molecular docking analysis. The results suggested that the synthetic derivatives may be potential towards the monoamine oxidase isozymes. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Alzheimer is a neurodegenerative disease and requires the development of new scaffold to treat it. In this regard, thiazoles derivative are playing their significant role. In the current research paper we have focused our attention for the development of tetrasubstituted thiazole (3a-h) derivatives using domino synthesis by mixing the thiourea as a precursor, with acetophenone in the presence of iodine and tosic acid in DMSO and refluxed for 12–22 h. The structures of the newly synthesized compounds were confirmed by FTIR, 1 H NMR, 13 C NMR and EIMS analysis. Thiazole derivatives were analyzed for their biological significances against acetyl and butylcholinesterase enzymes and compound 3b and 3d were found more active against these enzyme, respectively. The mode of inhibition was determined for the potent compounds against both the enzymes. Moreover, the molecular docking studies were carried out to explore the interactive behavior of the compounds within the active pocket of enzymes. Furthermore, the derivatives (3a-h) were evaluated for their anticancer potential against HeLa cancer cell lines. Most potent inhibition was observed by compound 3b . [ABSTRACT FROM AUTHOR]

A series of palladium (II) complexes ( 1–8 ) with N-(acyl)-N′,N′-(disubstituted) thioureas and phosphine ligands were synthesized and characterized by FT-IR, multinuclear ( 1 H, 13 C & 31 P) NMR spectroscopy and elemental analysis. The crystal structures of the Pd(II) complexes ( 1 ) & ( 5 ) of the type Pd II (L- O , S )(Ĺ- P )Cl were determined by single crystal X-ray diffraction analysis. They adopted the square planar geometry, where the N-(acyl)-N′, N′-(disubstituted) thioureas showed bidentate coordination mode in a chelating fashion through O and S donor atoms, and phosphine ligands through P atom at palladium centre. In vitro cytotoxic profile of the synthesized palladium(II) complexes ( 1–8 ) was determined against lung squamous carcinoma and breast adenocarcinoma cell lines. These complexes were also tested for promastigote forms of Leishmania tropica to evaluate their antileishmanial activity. The complexes bearing 2,4-dichlorophenyl moiety among the screened complexes were the most active with IC 50 values 1.72 ± 0.27, 2.12 ± 0.44, 1.57 ± 0.16 µM against the targets MDA-MB-231, H-157, Leishmania tropica , respectively. [ABSTRACT FROM AUTHOR]

In the present study, we have designed and synthesized a Schiff base derivative 3 and characterized by FT-IR, 1 H and 13 C NMR spectroscopy. Single crystal X-ray diffraction and NMR studies were also performed. The synthetic compound was screened for its inhibitory potential against carbonic anhydrase II. The experimental results were validated by molecular docking and dynamic simulations of compound 3 in the active pocket of enzyme. Important binding interactions with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Moreover, supramolecular assembly of the title compound was analyzed by density functional theory (DFT) calculations. These studies rendered a more clear understanding for the demonstration of novel molecular mechanism involved in CA II inhibition by the synthesized compound. [ABSTRACT FROM AUTHOR]

Due to the immense importance of aryl indole nucleus, herein we report the palladium-catalyzed arylation of N -substituted 2-aryl indole utilizing Suzuki-Miyaura cross coupling methodology. The biological screening for cholinesterase inhibition of the resulted biaryl indole moieties was carried out to evaluate their pharmacological potential, expecting to involve the development of new therapeutics for various inflammatory, cardiovascular, gastrointestinal and neurological diseases. This research work also involved the use of utilization of microwave-assisted organic synthesis (MAOS) for the synthesis of Bischler-Möhlau indole which is further biarylated via palladium-catalyzed cross coupling reaction. All the synthetic compounds ( 3a-n ) were tested for cholinesterase inhibition and exhibited high level of AChE inhibitory activities. Interestingly, compounds 3m and 3n were found to be dual inhibitors, however, remaining compound exhibited no inhibitory activity against BChE. The biological potential of the resulted compounds was explained on the basis of molecular docking studies, performed against AChE and BChE, exploring the probable binding modes of most potent inhibitors. [ABSTRACT FROM AUTHOR]

Three series of 4-hydroxy- N ′ -[benzylidene/1-phenylethylidene]-2- H /methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9–11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC 50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy- N′ -(1-phenylethylidene)-2 H -benzo[ e ][1,2]thiazine-3-carbohydrazide 1,1-dioxide ( 9i ) with an IC 50 value of 0.11 ± 0.005 μM, whereas, methyl 4-hydroxy-2 H -benzo[ e ][1,2]thiazine-3-carboxylate 1,1-dioxide ( 3 ) was the most active MAO-B inhibitor with an IC 50 value of 0.21 ± 0.01 μM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability. [ABSTRACT FROM AUTHOR]

A series of fifteen N 4 -benzyl substituted 5-nitroisatin-3-thiosemicarbazones 5a – o was synthesized and evaluated for urease inhibitory, phytotoxic and cytotoxic influences. All the compounds proved to be highly potent inhibitors of the enzyme, showing inhibitory activity (IC 50 = 0.87 ± 0.25–8.09 ± 0.23 μM) much better than the reference inhibitor, thiourea (IC 50 = 22.3 ± 1.12 μM) and may thus act as persuasive leads for further studies. In phytotoxicity assay, twelve out of fifteen thiosemicarbazones tested i.e. 5a – e , 5g , 5i and 5k – o appeared to be active, exhibiting weak or non-significant (5–35%) growth inhibition at the highest tested concentrations (1000 or 500 μg/mL). In contrast, only one compound i.e. 5i was active in the brine shrimp ( Artemia salina ) lethality bioassay, demonstrating cytotoxic activity with LD 50 value 2.55 × 10 −5 M. Molecular docking studies of compounds 5a – o were also performed to identify their probable binding modes in the active site of the enzyme. [ABSTRACT FROM AUTHOR]

The series of cobalt(III) complexes ( 1a – 12a ) with N , N , N ′-trisubstituted acylthioureas were synthesized and characterized by FT-IR, and multinuclear ( 1 H and 13 C) NMR spectroscopy and LC–MS combined with elemental analysis. Crystal structure of cobalt(III) chelate of type Co(L- O , S ) 3 were determined by single crystal X-ray diffraction analysis. Complexes were adopted to have the octahedral geometry, where the fac -disposed N , N , N ′-trisubstituted acylthioureas showed bidentate mode of coordination environment at cobalt centre defined by three O and three S donor atoms. The ligands are coordinated in a chelate fashion, forming three five-membered rings. The synthesized complexes were screened against Jack bean urease. In vitro anticancer activity against lung carcinoma (H-157), and kidney fibroblast (BHK-21) cell lines of the synthesized compounds were also studied and found them potent candidates for drugs. Cytotoxic results revealed that compound 10a was emerged as a leading member with an IC 50 value of 0.75 ± 0.027 μM against H-157 cell lines. When synthesized compounds were tested for antileishmanial activity against the promastigote forms of Leishmania major , compound 4a was identified as the most potent and lead candidate showed highest inhibition with an IC 50 value of 0.45 ± 0.053 μM. [ABSTRACT FROM AUTHOR]

• The unprecedented metal-free synthesis of tetracyclic heterocycle fused sultams. • DFT investigations were performed to elucidate the mechanism. • Good functional group tolerance and broad substrate scope. • Operationally simple synthesis of valuable products of medicinal interest. • X-ray characterization of intermediate and selective products. Polycyclic sultams are widely encountered in both natural products and bioactive drug candidates. In cognizance to their synthetic and medicinal chemistry applications, the exploration of facile approaches remains at high demand. In the present work, a straightforward, efficient and operationally simple methodology has been developed. The coupling of β -chloroaldehyde with a diverse range of anilines as bis-nucleophile containing N C C fragment was achieved to deliver a sulfostyril-quinoline hybrid framework. The formation of target scaffolds bearing various substituents avoiding the need of column chromatographic purification represents one of the key advantages associated with this transformation. The exclusive regioselectivity achieved for the formation of linear tetracyclic products over angular products was corroborated with density functional theory (DFT) calculations as well as single crystal X-ray analysis. Furthermore, the density functional theory calculations allowed us to understand the formation of tetracyclic sulfostyril-quinoline hybrid skeleton, and are in fair agreement with the observed regioselectivity of this reaction. The coupling of β -chloroaldehyde with a diverse range of anilines as bis-nucleophile containing N C C fragment was achieved to deliver a sulfostyril-quinoline hybrid framework. Computational (DFT) analysis reinforced the exclusive regioselectivity obtained in this transformation. [Display omitted] [ABSTRACT FROM AUTHOR]

Binding interactions of compound 5e in h-IAP (left) and compound 5e h-TNAP (right) showing competitive mode of inhibition in both the enzymes. • New thiazoles obtained by heterocyclization of thiosemicarbazides. • Thiazoles (5a-l) were subjected to h -TNAP and h -IAP assay. • Molecular docking of 5e and 5f explored the binding interactions. • MD Simulations showed stability of protein in apo and holo state. Alkaline phosphatases (APs) are a class of homodimeric enzymes which physiologically possess the dephosphorylation ability. APs catalyzes the hydrolysis of monoesters into phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are nitrogen and sulfur containing aromatic heterocycles considered as effective APs inhibitors. In this context, the current research paper presents the successful synthesis, spectroscopic characterization and in vitro alkaline phosphatase inhibitory potential of new thiazole derivatives. The structure activity relationship and molecular docking studies were performed to find out the binding modes of the screened compounds with the target site of tissue non-specific alkaline phosphatase (h -TNAP) as well as intestinal alkaline phosphatase (h -IAP). Compound 5e was found to be potent inhibitor of h -TNAP with IC 50 value of 0.17 ± 0.01 µM. Additionally, compounds 5a and 5i were found to be highly selective toward h -TNAP with IC 50 values of 0.25 ± 0.01 µM and 0.21 ± 0.02 µM, respectively. In case of h -IAP compound 5f was the most potent inhibitor with IC 50 value of 1.33 ± 0.10 µM. The most active compounds were resort to molecular docking studies on h -TNAP and h -IAP to explore the possible binding interactions of enzyme-ligand complexes. Molecular dynamic simulations were carried out to investigate the overall stability of protein in apo and holo state. [ABSTRACT FROM AUTHOR]

• Six new pyridine-pyrazole-benzenethiourea and pyridine-pyrazole-benzenesulfonamides were designed and synthesized. • They were investigated as inhibitors of human ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1 and −3). • IC 50 values of compounds 1d and 1e against ENPP1 are 0.18 and 0.40 µM, respectively. • IC 50 value of compound 1b against ENPP3 is 0.21 µM. • IC 50 values of compound 1e against MCF-7 cancer cell line is 16.05 µM with 24.43 times selectivite than BHK-21 normal cells. A series of six compounds (1a - f) possessing pyridine-pyrazole-benzenethiourea or pyridine-pyrazole-benzenesulfonamide scaffold were synthesized. The target compounds were screened to evaluate their inhibitory effect on human nucleotide pyrophosphatase/phosphodiesterase 1 and −3 (ENPP1 and ENPP3) isoenzymes. Compounds 1c-e were the most potent inhibitors of ENPP1 with sub-micromolar IC 50 values (0.69, 0.18, and 0.40 µM, respectively. Moreover, compound 1b was the most potent inhibitor of ENPP3 (IC 50 = 0.21 µM). They were much more potent than the reference standard inhibitor, suramin (IC 50 values against ENPP1 and −3 were 7.77 and 0.89 µM, respectively). Furthermore, all the six compounds were investigated for cytotoxic effect against cancerous cell lines (HeLa, MCF-7, and 1321N1) and normal cell line (BHK-21). Compound 1e was active against all the three cancer cell lines, however, showed preferential cytotoxicity against MCF-7 (IC 50 = 16.05 µM), which is comparable to the potency of cisplatin. All the tested compounds exhibited low or negligible cytotoxic effect against the normal cells. They have the merit of superior selectivity towards cancer cells than normal cells compared to cisplatin. The relative selectivity and potency of the inhibitors was justified by molecular docking studies. All the docked structures showed considerable binding interactions with amino acids residues of active sites of ENPP isoenzymes. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, a progressive chronic disease, characterized by the abnormal carbohydrate metabolism is associated with severe health complications including long term dysfunction or failure of several organs, cardiovascular and micro-angiopathic problems (neuropathy, nephropathy, retinopathy). Despite the existence of diverse chemical structural libraries of α -glucosidase inhibitors, the limited diabetic treatment due to the adverse side effects such as abdominal distention, flatulence, diarrhoea, and liver damage associated with these inhibitors encourage the medicinal research community to design and develop new and potent inhibitors of α -glucosidase with better pharmacokinetic properties. In this perspective, we demonstrate the successful integration of common functional groups (ketone & ester) in one combined pharmacophore which is favorable for the formation of hydrogen bonds and other weaker interactions with the target proteins. These keto ester derivatives were screened for their α -glucosidase inhibition potential and the in vitro results revealed compound 3c as the highly active inhibitor with an IC 50 value of 12.4 ± 0.16 μM compared to acarbose (IC 50 = 942 ± 0.74 μM). This inhibition potency was ~76-fold higher than acarbose. Other potent compounds were 3f (IC 50 = 28.0 ± 0.28 μM), 3h (IC 50 = 33.9 ± 0.09 μM), 3g (IC 50 = 34.1 ± 0.04 μM), and 3d (IC 50 = 76.5 ± 2.0 μM). In addition, the emerging use of carbonic anhydrase inhibitors for the treatment of diabetic retinopathy (a leading cause of vision loss) prompted us to screen the keto ester derivatives for the inhibition of carbonic anhydrase-II. Compound 3b was found significantly active against carbonic anhydrase-II with an IC 50 of 16.5 ± 0.92 μM (acetazolamide; IC 50 = 18.2 ± 1.23 μM). Compound 3a also exhibited comparable potency with an IC 50 value of 18.9 ± 1.08 μM. Several structure-activity relationship analyses depicted the influence of the substitution pattern on both the aromatic rings. Molecular docking analysis revealed the formation of several H-bonding interactions through the ester carbonyl and the nitro oxygens of 3c with the side chains of His348, Arg212 and His279 in the active pocket of α -glucosidase whereas 3b interacted with His95, -OH of Thr197, Thr198 and WAT462 in the active site of carbonic anhydrase-II. Furthermore, evaluation of ADME properties suggests the safer pharmacological profile of the tested derivatives. The present study investigates the dual inhibitory potential of a series of keto ester derivatives against α -glucosidase and carbonic anhydrase-II enzymes. Unlabelled Image • New structural libraries of compounds were prepared to treat diabetes mellitus and diabetic retinopathy. • Keto esters 3a–m were investigated as potent inhibitors of α -glucosidase and carbonic anhydrase-II enzymes. • Compound 3c was identified as the most potent inhibitor of α -glucosidase enzyme. • Compound 3b inhibited the carbonic anhydrase-II with an IC 50 of 16.5 ± 0.92 μM. • Molecular docking, enzyme kinetics, and detailed ADMET properties were also investigated. [ABSTRACT FROM AUTHOR]

The overlap of all the docked inhibitors (1 (brown), 2 (red), 5 (pink) and 7 (yellow)) inside the active site of acetylcholinesterase. • Synthesis of 1,2,4-triazole-3-thione amine substituted thioureas. • Synthesis of 1–4-aminophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-isobutylphenyl)propan-1-one. • Investigation of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) inhibition assays. Owing to the desperate need of new drugs development to treat Alzheimer's ailment the synthesis of 1-aroyl-3-(5-(4-chlorophenyl)-1,2,4-triazole-3-thioneaminylthioureas (2 – 6) starting from (4-amino-5-(4-chlorophenyl)-4 H -1,2,4-triazole-3-thiol) (1) and synthesis of 1-(3-(4-aminophenyl)-5-phenyl-4,5-dihydro-1 H -pyrazol-1-yl)-2-(4-isobutylphenyl)propan-1-one (7 – 9) starting from 2-(4-isobutylphenyl)propanehydrazide (a) with the cyclization with substituted chalcones (c-e) was carried out. To check the biological potential of the synthesized compounds, all were subjected to acetylcholinesterase (AChE) and butrylcholinesterase (BChE) inhibition assays. The most potent and selective inhibitor for the acetylcholinesterase was compound 7 having an inhibitory concentration of 123 ± 51 nM, whereas, compound 6 was found as selective inhibitor of butyrylcholinesterase (BChE) with an IC 50 value of 201 ± 80 nM. However, the compounds 1 and 2 were found as dual inhibitors i.e. active against both acetylcholinesterase as well as butyrylcholinesterase. [ABSTRACT FROM AUTHOR]

The line representation (pink color) of active cavity of h CAXII, in complex with the selective and most potent inhibitor 1d shown in stick representation. In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a–t , having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH 2 , NHMe, or NMe 2) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified h CAII, IX and XII isoforms. The most potent inhibitors for h CAII, h CAIX and h CAXII were 1g , 1b and 1d with an IC 50 ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against h CAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions. [ABSTRACT FROM AUTHOR]

Docking pose of compound 1x into the crystal structure of NPP3. A new series of sulfonate derivatives 1a – zk were synthesized and evaluated as inhibitors of nucleotide pyrophosphatases. Most of the compounds exhibited good to moderate inhibition towards NPP1, NPP2, and NPP3 isozymes. Compound 1m was a potent and selective inhibitor of NPP1 with an IC 50 value of 0.387 ± 0.007 µM. However, the most potent inhibitor of NPP3 was found as 1x with an IC 50 value of 0.214 ± 0.012 µM. In addition, compound 1e was the most active inhibitor of NPP2 with an IC 50 value of 0.659 ± 0.007 µM. Docking studies of the most potent compounds were carried out, and the computational results supported the in vitro results. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of benzohydrazide derivatives 1 – 43. • Urease inhibitory activity of synthesized derivatives have been evaluated. • Kinetic study of the active has been performed. • The in silico study of the active compounds was also done. Abstract Benzohydrazide derivatives 1 – 43 were synthesized via "one-pot" reaction and structural characterization of these synthetic derivatives was carried out by different spectroscopic techniques such as 1H NMR and EI-MS. The synthetic molecules were evaluated for their in vitro urease inhibitory activity. All synthetic derivatives showed good inhibitory activities in the range of (IC 50 = 0.87 ± 0.31–19.0 ± 0.25 µM) as compared to the standard thiourea (IC 50 = 21.25 ± 0.15 µM), except seven compounds 17 , 18 , 23 , 24 , 29 , 30 , and 41 which were found to be inactive. The most active compound of the series was compound 36 (IC 50 = 0.87 ± 0.31 μM) having two chloro groups at meta positions of ring A and methoxy group at para position of ring B. The structure–activity relationship (SAR) of the active compounds was established on the basis of different substituents and their positions in the molecules. Kinetic studies of the active compounds revealed that compounds can inhibit enzyme via competitive and noncompetitive modes. In silico study was also performed to understand the binding interactions of the molecules (ligand) with the active site of enzyme. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Anthocleista vogelii Planch is a medicinal plant traditionally used in West Africa for the management and treatment of diabetes mellitus. Aim of the study To determine the antidiabetic activities of chloroform fraction (CF) of Anthocleista vogelii Planch root bark in rats with diet- and alloxan-induced obesity-diabetes. Materials and methods Inhibitory activities of CF against α-amylase and α-glucosidase activities were determined in vitro. Three weeks old rats were fed with high-fat diet for 9 weeks to induce obesity prior to further induction of diabetes using alloxan (150 mg/kg body weight, i.p.). Blood glucose levels and body weight were measured every 7 days throughout the experiment. Glucose tolerance was assessed in normal and CF-treated rats on day 21. Terminal blood samples were collected from sacrificed animals for the measurement of serum insulin levels. Pancreases were excised from treated and untreated animals for histopathological examination. Results LCMS/MS chromatographic profile of CF via positive and negative modes revealed 13 and 23 compounds respectively. Further analysis revealed quebrachitol (QCT), loganin, sweroside, oleoside 11-methyl ester and ferulic acid, which have been previously reported for their antidiabetic activities, as constituents of CF. CF inhibited activities of α-amylase (IC 50 = 51.60 ± 0.92 µg/ml) and α-glucosidase (IC 50 = 5.86 ± 0.97 µg/ml) in a dose-dependent manner. Treatment of animals with obesity-diabetes with 100 and 200 mg/kg CF significantly improved glucose tolerance (P < 0.001) and enhanced serum insulin levels (P < 0.05) compared to diabetic control rats. Conclusions Antidiabetic activities of CF might be mediated via inhibition of α-amylase and α-glucosidase activities, elevation of serum insulin concentration, and enhancement of insulin and leptin sensitivity in obesity-diabetes rats. This study further substantiates the traditional use of A. vogelii in the management and treatment of diabetes in Africa and encourages further studies to investigate its mechanism of action. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

A series of fifteen N4-benzyl substituted 5-chloroisatin-3-thiosemicarbazones 5a-o were synthesized and screened mainly for their antiurease and antiglycation effects. Lemna aequinocitalis growth and Artemia salina assays were carried out to determine their phytotoxicity and cytotoxicity potential. All the compounds proved to be extremely effective urease inhibitors, demonstrating enzyme inhibition much better than the reference inhibitor, thiourea (IC50 values 1.31 ± 0.06 to 3.24 ± 0.15 vs. 22.3 ± 1.12 µM). On the other hand, eight out of fifteen compounds tested, i.e. 5b, 5c, 5h-k, 5m and 5n were found to be potent glycation inhibitors. Of these, five viz. 5c, 5h-j and 5n proved to be exceedingly efficient, displaying glycation inhibition greater than the reference inhibitor, rutin (IC50 values 114.51 ± 1.08 to 229.94 ± 3.40 vs. 294.5 ± 1.5 µM). [ABSTRACT FROM AUTHOR]

A series of iminothiazolines ( 4a–j ) featuring 2,4,5 - trichlorophenyl moiety and aroyl/heteroaroyl substituents has been prepared from readily accessible thioureas. In - vitro screening against glucosidase enzymes showed highly specific inhibition of α -glucosidase with a marked dependence of the potency upon the nature of the aroyl/heteroaroyl substituents. The most potent representatives, bearing ortho-tolyl and bulky naphthyl groups displayed the highest inhibitory potential with IC 50 value of 0.15 ± 0.01 µM compared to standard drug acarbose (IC 50 = 38.2 ± 0.12 µM). Several other derivatives ( 4c , 4d , 4i and 4j ) were also significantly powerful and selective inhibitors of α -glucosidase. Binding interactions of potent compounds 4b , 4c , 4h and 4i with α -glucosidase were explored by molecular docking simulation. These results clearly identified a new class of structural leads which can be further investigated for the development of promising α -glucosidase inhibitors for the prevention of diabetes mellitus. [ABSTRACT FROM AUTHOR]

The multifactorial nature of Parkinson’s disease necessitates the development of new chemical entities with inherent ability to address key pathogenic processes. To this end, two series of new symmetrical 1,2- and 1,4-bis(2-aroyl/alkoylimino-5-(2-methoxy-2-oxoethylidene)-4-oxo-thiazolidin-3-yl)benzene derivatives ( 3a–g and 5a–e ) were synthesized in good yields by the cyclization of 1,2- and 1,4-bis(N′-substituted thioureido)benzene intermediates with dimethyl acetylenedicarboxylate (DMAD) in methanol at ambient temperature. The bis-iminothiazolidinone compounds were investigated in vitro for their inhibition of monoamine oxidase (MAO-A & MAO-B) enzymes with the aim to identify new and distinct pharmacophores for the treatment of neurodegenerative disorders like Parkinson’s disease. Most of the designed compounds exhibited good inhibitory efficacy against monoamine oxidases. Compound 5a was identified as the most potent inhibitor of MAO-A depicting an IC 50 value of 0.001 μM, a 4-fold stronger inhibitory strength compared to standard inhibitor (clorgyline: IC 50 = 0.0045 μM). Molecular docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed inhibition towards monoamine oxidases. [ABSTRACT FROM AUTHOR]

[Display omitted] Structure-activity relationship of pyrazolo-pyridinol derivative (2) and thiadiazolo pyrimidinone derivative (13) with sitagliptin • Type 2 diabetes mellitus (T2DM) is widely prevalent metabolic disorder. • Dipeptidyl Peptidase 4 (DPP-4) inhibitors are proven to be anti-diabetic drugs. • The structure-based pharmacophore modeling has been employed. • Virtual screening of compound library. • In vitro assay and structure-activity relationship studies were carried out. Type 2 diabetes mellitus (T2DM) is one of the most widely prevalent metabolic disorders with no cure to date thus remains the most challenging task in the current drug discovery. Therefore, the only strategy to control diabetes prevalence is to develop novel efficacious therapeutics. Dipeptidyl Peptidase 4 (DPP-4) inhibitors are currently used as anti-diabetic drugs for the inhibition of incretins. This study aims to construct the chemical feature based on pharmacophore models for dipeptidyl peptidase IV. The structure-based pharmacophore modeling has been employed to evaluate new inhibitors of DPP-4. A four-featured pharmacophore model was developed from crystal structure of DPP-4 enzyme with 4-(2-aminoethyl) benzenesulfonyl fluoride in its active site via pharmacophore constructing tool of Molecular Operating Environment (MOE) consisting F1 Hyd (hydrophobic region), F2 Hyd|Cat|Don (hydrophobic cationic and donor region), F3 Acc (acceptor region) and F4 Hyd (hydrophobic region). The generated pharmacophore model was used for virtual screening of in-house compound library (the available compounds which were used for initial screening to get the few compounds for the current studies). The resultant selected compounds, after virtual screening were further validated using in vitro assay. Furthermore, structure-activity relationship was carried out for the compounds possessing significant inhibition potential after docking studies. The binding free energy of analogs was evaluated via molecular mechanics generalized Born surface area (MM-GBSA) and Poisson-Boltzmann surface area (MM-PBSA) methods using AMBER 16 as a molecular dynamics (MD) simulation package. Based on potential findings, we report that selected candidates are more likely to be used as DPP-4 inhibitors or as starting leads for the development of novel and potent DPP-4 inhibitors. [ABSTRACT FROM AUTHOR]

• 20 target compounds were investigated as inhibitors of human NPP1 and -3. • IC 50 value of compound 1n against NPP1 is 0.12 µM. • IC 50 value of compound 1f against NPP3 is 0.12 µM. • IC 50 value of compound 1r against MCF-7 cell line is 0.19 µM, 11.7 times selectivity towards MCF-7 than WI-38 normal cells. • Docking and enzyme kinetics studies were carried out to investigate the binding modes. Ectonucleotidases are a broad family of ectoenzymes that play a crucial role in purinergic cell signaling. Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) belong to this group and are important drug targets. In particular, NPP1 and NPP3 are known to be druggable targets for treatment of impaired calcification disorders (including pathological aortic calcification) and cancer, respectively. In this study, we investigated a series of sulfonate and sulfamate derivatives of benzofuran and benzothiophene as potent and selective inhibitors of NPP1 and NPP3. Compounds 1c , 1g , 1n , and 1s are the most active NPP1 inhibitors (IC 50 values in the range 0.12–0.95 µM). Moreover, compounds 1e , 1f , 1j , and 1l are the most potent inhibitors of NPP3 (IC 50 ranges from 0.12 to 0.95 µM). Compound 1d , 1f and 1t are highly selective inhibitors of NPP1 over NPP3, whereas compounds 1m and 1s are found to be highly selective towards NPP3 over NPP1. Structure-activity relationship (SAR) study has been discussed in detailed. With the aid of molecular docking studies, a common binding mode of these compounds and suramin (the standard inhibitor) was revealed, where the sulfonate group acts as a cation-binding moiety that comes in close contact with the zinc ion of the active site. Moreover, cytotoxic evaluation against MCF-7 and HT-29 cancer cell lines revealed that compound 1r is the most cytotoxic towards MCF-7 cell line with IC 50 value of 0.19 µM. Compound 1r is more potent and selective against cancer cells than normal cells (WI-38) as compared to doxorubicin. [ABSTRACT FROM AUTHOR]