Synthesis and biological evaluation of antitumour-active betulin derivatives

The reaction of betulinic aldehydes with various carbon nucleophiles gave a series of new betulin derivatives, among them epoxides, glycidic derivatives and β-hydroxy carbonyl compounds. Subsequent transformations of the β-hydroxy carbonyls lead to 1,3-diketo- and α,β-unsaturated betulin derivatives. These compounds were assayed for cytotoxicity using 15 human cancer cell lines and a colorimetric SRB-assay. Several compounds revealed significant antitumour activity.     

A double mutant of highly purified Geobacillus stearothermophilus lactate dehydrogenase recognises l-mandelic acid as a substrate

Lactate dehydrogenase from the thermophilic organism Geobacillus stearothermophilus (formerly Bacillus stearothermophilus) (bsLDH) has a crucial role in producing chirally pure hydroxyl compounds. α-Hydroxy acids are used in many industrial situations, ranging from pharmaceutical to cosmetic dermatology products. One drawback of this enzyme is its limited substrate specificity. For instance, l-lactate dehydrogenase exhibits no detectable activity towards the large side chain of 2-hydroxy acid l-mandelic acid, an α-hydroxy acid with anti-bacterial activity. Despite many attempts to engineer bsLDH to accept α-hydroxy acid substrates, there have been no attempts to introduce the industrially important l-mandelic acid to bsLDH. Herein, we describe attempts to change the reactivity of bsLDH towards l-mandelic acid. Using the Insight II molecular modelling programme (except ‘program’ in computers) and protein engineering techniques, we have successfully introduced substantial mandelate dehydrogenase activity to the enzyme. Energy minimisation modelling studies suggested that two mutations, T246G and I240A, would allow the enzyme to utilise l-mandelic acid as a substrate. Genes encoding for the wild-type and mutant enzymes were constructed, and the resulting bsLDH proteins were overexpressed in Escherichia coli and purified using the TAGZyme system. Enzyme assays showed that insertion of this double mutation into highly purified bsLDH switched the substrate specificity from lactate to l-mandelic acid.     

A new series of N2-substituted-5-(p-toluenesulfonylamino)phthalimide analogues as α-glucosidase inhibitors

Several members of a new family of non-sugar-type α-glycosidase inhibitors, bearing a 5-(p-toluenesulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and their activities were investigated. The newly synthesized compounds displayed different inhibition profile towards yeast α-glycosidase and rat intestinal α-glycosidase. Almost all the compounds had strong inhibitory activities against yeast α-glycosidase. Regarding rat intestinal α-glycosidase, only analogs with N2-aromatic substituents displayed varying degrees of inhibitory activities on rat intestinal maltase and lactase and nearly all compounds showed no inhibition against rat intestinal α-amylase. Structure–activity relationship studies indicated that 5-(p-toluenesulfonylamino)phthalimide moiety is a favorable scaffold to exert the α-glucosidase inhibitory activity and substituents at the N2 position have considerable influence on the efficacy of the inhibition activities.     

Reduction by a model of NAD(P)H: XI. Stereochemistry of a lactate dehydrogenase-model reaction

Stereochemistry of the biomimetic reduction of α-keto esters with NAD(P)H-model compounds has been investigated. The model compound with the R-configuration reduces the α-keto esters to the (R)-α-hydroxy esters, whereas (S)-α-hydroxy esters are afforded by the reduction with the S-configurational model compounds. It has been concluded that pro-R and -S hydrogens of the model compounds with R- and S-configuration, respectively, contribute predominantly to the reduction.     

Biological evaluation of new imidazole derivatives tethered with indole moiety as potent α-glucosidase inhibitors

A series of triarylimidazoles substituted with 2-arylindoles (4a-4j) were prepared and evaluated for their in vitro α-Glucosidase inhibition. α-Glucosidase inhibition assay displayed a new class of highly potent agents The new compounds showed significant α-glucosidase inhibitory activity as compared to the standard inhibitor acrabose. Structures of synthesized compounds were determined by using Mass spectrometry FT-IR, ¹H NMR and ¹³C NMR.     

Organocatalyzed solvent free an efficient novel synthesis of 2,4,5-trisubstituted imidazoles for α-glucosidase inhibition to treat diabetes

A new and efficient solvent free synthesis of 2,4,5-trisubstituted imidazoles (3a–3j) was achieved by N-acetyl glycine (NAG) catalyzed three components condensation of aldehydes, benzil and ammonium acetate. Our synthetic methodology accommodated a range of various substituted alkyl and aryl aldehydes. Evaluation of α-glucosidase inhibitory activity of these imidazole derivatives revealed that most of them presented good α-glucosidase inhibition at low micro-molar concentrations. Among the synthesized compounds, compound 3c, bearing the ortho-hydroxy phenyl substituent at position 2 displayed the highest inhibitory activity with an IC₅₀ value 74.32 ± 0.59 μM. In silico molecular docking for all compounds and computational studies of the most active compound 3c were also performed.     

Design,synthesis, and in vitro evaluation of quinolinyl analogues for α-synuclein aggregation

Here we report the synthesis and in vitro evaluation of 25 new quinolinyl analogues for α-synuclein aggregates. Three lead compounds were subsequently labeled with carbon-11 or fluorine-18 to directly assess their potency in a direct radioactive competitive binding assay ng both α-synuclein fibrils and tissue homogenates from Alzheimer’s disease (AD) cases. The modest binding affinities of these three radioligands toward α-synuclein were comparable with results from the Thioflavin T fluorescence assay. However, all three ligand also showed modest binding affinity to the AD homogenates and lack selectivity for α-synuclein. The structure–activity relationship data from these 25 analogues will provide useful information for design and synthesis of new compounds for imaging α-synuclein aggregation.     

Serendipitous discovery of α-hydroxyalkyl esters as β-lactamase substrates

O-(1-Carboxy-1-alkyloxycarbonyl) hydroxamates were found to spontaneously decarboxylate in aqueous neutral buffer to form O-(2-hydroxyalkylcarbonyl) hydroxamates. While the former molecules do not react rapidly with serine β-lactamases, the latter are quite good substrates of representative class A and C, but not D, enzymes, and particularly of a class C enzyme. The enzymes catalyze hydrolysis of these compounds to a mixture of the α-hydroxy acid and hydroxamate. Analogous compounds containing aryloxy leaving groups rather that hydroxamates are also substrates. Structure-activity experiments showed that the α-hydroxyl group was required for any substantial substrate activity. Although both d- and l-α-hydroxy acid derivatives were substrates, the former were preferred. The response of the class C activity to pH and to alternative nucleophiles (methanol and d-phenylalanine) suggested that the same active site functional groups participated in catalysis as for classical substrates. Molecular modeling was employed to explore how the α-hydroxy group might interact with the class C β-lactamase active site. Incorporation of the α-hydroxyalkyl moiety into novel inhibitors will be of considerable interest.     

Design,synthesis, in vitro,and in silico studies of novel diarylimidazole-1,2,3-triazole hybrids as potent α-glucosidase inhibitors

In this work, new derivatives of diarylimidazole-1,2,3-triazole 7a-p were designed, synthesized, and evaluated for their in vitro α-glucosidase inhibitory activity. All compounds showed potent inhibitory activity in the range of IC₅₀ = 90.4–246.7 µM comparing with acarbose as the standard drug (IC₅₀ = 750.0 µM). Among the synthesized compounds, compounds 7b, 7c, and 7e were approximately 8 times more potent than acarbose. The kinetic study of those compounds indicated that they acted as the competitive inhibitors of α-glucosidase. Molecular docking studies were also carried out for compounds 7b, 7c, and 7e using modeled α-glucosidase to find the interaction modes responsible for the desired inhibitory activity.     

Anticancer and antimicrobial glycosides from ipomoea bahiensis

Four new antimicrobial glycosides have been isolated from Ipomoea bahiensis. Spectroscopic properties and basic and acidic hydrolysis characterized them as derivatives of 11 -hydroxy hexadecanoic and 11-hydroxy tetradecanoic acid, glycosidically linked in the 11-position to a trisaccharide unit composed of glucose, rhamnose and fucose which is esterified by tiglic and 3-hydroxy-2-methylbutyric acid. One of these compounds revealed significant activity against Sarcoma 180 in mice.     

Rational drug design and synthesis of new α-Santonin derivatives as potential COX-2 inhibitors

Sesquiterpene compounds are widely known for their numerous pharmacological activities. Herein the focus of the authors was on α-Santonin, a sesquiterpene lactone from the Artemisia genus: the aim was to determine whether α-Santonin could be considered in the treatment of inflammation and pain. To this purpose, a small series of derivatives was designed and screened in silico against the enzyme COX-2 along with the parent compound. Drug-likeness parameters were also assessed. The compounds were eventually synthesized, and few were tested to determine their efficacy in the inhibition of COX-2 activity and expression. Overall, compound A2 was the only one with a detectable inhibitory potential of COX-2 activity whilst two of its ether derivatives demonstrated improved ability in the inhibition of COX-2 expression.     

Application of α- and β-naphthoflavones as monooxygenase inhibitors of Absidia coerulea KCh 93, Syncephalastrum racemosum KCh 105 and Chaetomium sp. KCh 6651 in transformation of 17α-methyltestosterone

In this work, 17α-methyltestosterone was effectively hydroxylated by Absidia coerulea KCh 93, Syncephalastrum racemosum KCh 105 and Chaetomium sp. KCh 6651. A. coerulea KCh 93 afforded 6β-, 12β-, 7α-, 11α-, 15α-hydroxy derivatives with 44%, 29%, 6%, 5% and 9% yields, respectively. S. racemosum KCh 105 afforded 7α-, 15α- and 11α-hydroxy derivatives with yields of 45%, 19% and 17%, respectively. Chaetomium sp. KCh 6651 afforded 15α-, 11α-, 7α-, 6β-, 9α-, 14α-hydroxy and 6β,14α-dihydroxy derivatives with yields of 31%, 20%, 16%, 7%, 5%, 7% and 4%, respectively. 14α-Hydroxy and 6β,14α-dihydroxy derivatives were determined as new compounds. Effect of various sources of nitrogen and carbon in the media on biotransformations were tested, however did not affect the degree of substrate conversion or the composition of the products formed. The addition of α- or β-naphthoflavones inhibited 17α-methyltestosterone hydroxylation but did not change the percentage composition of the resulting products.     

Discovery of 2-aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-ones as novel EGFR inhibitor by scaffold hopping

2-Aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-one has been proposed as a novel scaffold of EGFR inhibitor based on scaffold hoping. In the present study, a series of 2-aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-one derivatives were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against two human cancer cell lines, including A431 and A549. The SAR of the title compounds was preliminarily discussed. The compounds with ideal inhibition were evaluated through ELISA-based EGFR-TK assay. Compound 6c showed the best activity against A431 and EGFR tyrosine kinase. These findings suggest that title compounds are EGFR inhibitors with novel structures.     

Evaluation of the antioxidant activity of flavonoids by “ferric reducing antioxidant power” assay and cyclic voltammetry

Flavonoids, naturally occurring phenolic compounds, have recently been studied extensively for their antioxidant properties. The structure–antioxidant activity relationships (SAR) of flavonoids have been evaluated against different free radicals, but “ferric reducing antioxidant power” (FRAP) assay, which determines directly the reducing capacity of a compound, has not been used for this purpose. In this study, the antioxidant activities of 18 structurally different flavonoids were evaluated by FRAP assay modified to be used in 96-well microplates. Furthermore, their oxidation potentials were also measured, which were in the range of +0.3 V (myricetin) to +1.2 V (5-hydroxy flavone) and were in good agreement with FRAP assay results. Quercetin, fisetin and myricetin had the lowest oxidation potentials and appeared the most active compounds in FRAP assay and were 3.02, 2.52 and 2.28 times more active than Trolox, respectively. Indications were found that the o-dihydroxy structure in the B ring and the 3-hydroxy group and 2,3-double bond in the C ring give the highest contribution to the antioxidant activity.     

New furanoflavanoids,intestinal α-glucosidase inhibitory and free-radical (DPPH) scavenging,activity from antihyperglycemic root extract of Derris indica (Lam.)

A bioassay-guided fractionation and chemical examination of antihyperglycemic root extract of Derris indica resulted in isolation and characterization of two new furanoflavanoids (1, 2) along with thirteen known compounds (3–15). Their structures were determined on the basis of extensive spectroscopic (IR, MS, 1D and 2D NMR) data analysis and by comparison with the literature data. All the compounds were tested in vitro for intestinal α-glucosidase inhibitory and DPPH radical activity. New compounds (1, 2) displayed moderate intestinal α-glucosidase inhibitory as well as free radical scavenging activity. Other compounds also displayed varying degrees of moderate intestinal α-glucosidase inhibitory activity. Pongamol (6) displayed potent intestinal α-glucosidase inhibition.     

Incrassamarin A–D: Four new 4-substituted coumarins from Calophyllum incrassatum and their biological activities

Four new 4-substituted coumarins, incrassamarin A (1), B (2), C (3) and D (4) with (7S,8S)-7,8-dihydro-5-hydroxy-7,8-dimethyl-4-propyl-2H,6H-benzo[1,2-b;5,4-b’]dipyran-2,6-dione (5), friedelin, carpachromene, amentoflavone, epiafzelechin and L-quercitrin were isolated from the barks and leaves of Calophyllum incrassatum (Guttiferae). The compounds were isolated and purified by size-exclusion recycling HPLC and column chromatographic techniques. The structures of the compounds were determined by spectroscopic means. The compounds were tested for their cytotoxic activity towards MCF-7 and A-549 cell lines and α-glucosidase enzymatic inhibitory activity. Compound (1) displayed cytotoxic activity against A-549 cell lines with IC₅₀ 87.71 μg/mL and showed inhibition towards α-glucosidase enzymatic activity with IC₅₀ 93.25 μM. This is the first report on the isolation of phytochemicals from the barks and leaves of C. incrassatum and their bioactivities.     

Phenylhydrazides as inhibitors of Leishmania amazonensis arginase and antileishmanial activity

Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of α,α-difluorohydrazide and α,α-difluoramides against Leishmania amazonensis arginase (LaArg). Four α,α-difluorohydrazide derivatives showed activity against LaArg with K_i in the range of 1.3–26 μM. The study of the kinetics of LaArg inhibition showed that these substances might act via different inhibitory mechanisms or even by a combination of these. The compounds were tested against L. amazonensis promastigotes and the best result was obtained to the compound 4 (EC₅₀ of 12.7 ± 0.3 μM). In addition, in order to obtain further insight into the binding mode of such compounds, molecular docking studies were performed to obtain additional validation of experimental results. Considering these results, it is possible to conclude that α,α-difluorohydrazide derivatives are a promising scaffold in the development of new substances against the etiological agent of leishmaniasis by targeting LaArg.     

Design,synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, β- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69–9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and β-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for β-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for β-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.     

ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors

The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the in vivo biodistribution of HA-conjugated GGDPS inhibitors.     

Inhibitory potential of proanthocyanidins from the fruit pulp of Clausena lansium (Lour.) Skeels against α-glucosidase and non-enzymatic glycation: Activity and mechanism

Inhibiting the activity of α-glucosidase and glycosylation of protein is an important way to treat diabetes mellitus and its complications. In this study, we investigated the anti-α-glucosidase activity, anti-glycation potential and structure of proanthocyanidins from fruit pulp of Clausena lansium (Lour.) Skeels. C. lansium fruit pulp proanthocyanidins showed a remarkable inhibition against α-glucosidase activity with IC₅₀ vaule of 0.26 ± 0.01 μg/mL in a competitive manner, and quenched the fluorescence of α-glucosidase by forming proanthocyanidin-α-glucosidase complex. Furthermore, compared to positive agent aminoguanidine (AG), the proanthocyanidins were the more significant inhibitors of non-enzymatic glycation by strongly inhibiting the formation of α-dicarbonyl compounds and advanced glycation end products. In addition, the structure of the proanthocyanidins was characterized in detail. These compounds were mainly composed of prodelphinidins, and their gallates. The main extender units, gallocatechin epigallocatechin and their gallates, were critical factor of the strong anti-α-glucosidase and anti-glycation activity. Therefore, this study authenticated a efficient α-glucosidase inhibitors and antiglycation agents, which would contribute to the development of anti-diabetic drug.