Dibenzazepine-linked isoxazoles: New and potent class of α-glucosidase inhibitors.

α-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33-54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 µM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 µM). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48-50, and 54 showed binding interactions with critical amino acid residues of α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.

Microwave-Assisted Organic Synthesis, structure-activity relationship, kinetics and molecular docking studies of non-cytotoxic benzamide derivatives as selective butyrylcholinesterase inhibitors.

A series of benzamide derivatives 1-12 with various functional groups (-H, -Br, -F, -OCH3, -OC2H5, and -NO2) was synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) activity in vitro. Structure-activity relationship showed that the substitution of -Br group influenced the inhibitory activity against BCHE enzyme. Synthesized compounds were found to be selective inhibitors of BCHE. In addition, all compounds 1-12 were found to be non-cytotoxic, as compared to the standard cycloheximide (IC50 = 0.8 ±â€¯0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ±â€¯0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ±â€¯0.37 µM). Enzyme kinetic studies indicated that compounds 1, 3-4, and 7-8 showed a mixed mode of inhibition against BCHE, while compounds 2, 5-6 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329, and many others.

New carbazole linked 1,2,3-triazoles as highly potent non-sugar α-glucosidase inhibitors.

In the present study, a series of new carbazole linked 1H-1,2,3-triazoles (2-27) were synthesized via click reaction of N-propargyl-9H-carbazole (1) and azides of appropriate acetophenones and heterocycles. Synthesized carbazole triazoles including 7, 9, 10, 19, 20, and 23-26 (IC50=0.8±0.01-100.8±3.6µM), exhibited several folds more potent α-glucosidase inhibitory in vitro activity as compared to standard drug, acarbose. Compounds 2-5, 7-13, and 17-27 did not show any cytotoxicity against 3T3 cell lines, except triazoles 6, and 14-16. Among the series, carbazole triazoles 23 (IC50=1.0±0.057µM) and 25 (IC50=0.8±0.01µM) were found to be most active, and could serve as an attractive building block in the search of new non-sugar derivatives as anti-diabetic agents.

Synthesis of a Library of 1,5,2-Dithiazepine 1,1-Dioxides. Part 1: A One-Pot Sulfonylation/Thia-Michael Protocol.

A novel one-pot sulfonylation/intramolecular thia-Michael protocol is reported for the synthesis of 1,5,2-dithiazepine 1,1-dioxides. Sulfonylation between cysteine ethyl ester/cysteamine and 2-chloroethanesulfonyl chloride, followed by in situ intramolecular thia-Michael addition, was achieved and afforded the titled 1,5,2-dithiazepine-1,1-dioxide scaffolds. Diversification was demonstrated for future library synthesis.

Synthesis of a Library of 1,5,2-Dithiazepine 1,1-Dioxides. Part 2: Routes to Bicyclic Sultams.

The synthesis of a library of bicyclic sultams incorporating the 1,5,2-dithiazepine 1,1-dioxide moiety is reported. Following scaffold synthesis via a one-pot sulfonylation/intramolecular thia-Michael protocol, several additional cyclization strategies have been realized enabling access to new bicyclic sultams.

4-Meth-oxy-N-(4-meth-oxy-2-nitro-phen-yl)benzamide.

In the title compound, C(15)H(14)N(2)O(5), the central amide C-C(=O)-N-C unit forms dihedral angles of 28.17 (13) and 26.47 (13)° with the two benzene rings, whereas the two benzene rings are almost coplanar, making a dihedral angle of 4.52 (13)°. The two meth-oxy and the nitro substituents are almost coplanar with their attached benzene rings, with C-O-C-C torsion angles of -1.3 (4) and -4.6 (4)°, and an O-N-C-C torsion angle of 17.1 (3)°. In the crystal, mol-ecules are linked via C-H⋯O and N-H⋯O inter-actions, forming a tape running along the b axis.

2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-fluoro-benzoate.

In the title compound, C(13)H(12)FN(3)O(4), the dihedral angle between the benzene and imidazole rings is 32.77 (12)°. In the crystal, mol-ecules are linked into a three-dimensional network by C-H⋯O hydrogen bonds.

2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 2-bromo-benzoate.

In the title compound, C(13)H(12)BrN(3)O(4), the dihedral angle between the benzene and imidazole rings is 30.6 (2)°. In the crystal, mol-ecules are linked into chains parallel to [001] by C-H⋯O hydrogen bonds. The crystal packing is further consolidated by π-π inter-actions [centroid-centroid distance = 3.482 (2) Å].

2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl methane-sulfonate.

The asymmetric unit of the title compound, C(7)H(11)N(3)O(5)S, contains two independent mol-ecules with virtually identical conformations. The imidazole rings of both mol-ecules are essentially planar (r.m.s. deviations = 0.0019 and 0.0038 Å), with a dihedral angle 9.25 (19)° between them. The nitro groups are oriented at 4.5 (2) and 6.44 (13)° with respect to the imidazole rings. In the crystal, mol-ecules are linked to form a three-dimensional framework by C-H⋯O and C-H⋯N hydrogen bonds.

2-Azido-1-(4-fluoro-phen-yl)ethanone.

The crystal structure of the title compound, C(8)H(6)FN(3)O, is stabilized by C-H⋯O hydrogen bonds, which link the mol-ecules into chains running parallel to the a axis.

2-Azido-1-(4-methyl-phen-yl)ethanone.

In the mol-ecule of the title compound, C(9)H(9)N(3)O, the angle formed by the least-squares line through the azide group with the normal to the plane of the benzene plane ring is 46.62 (16)°. The crystal structure features C-H⋯O hydrogen bonds, which link the mol-ecules into zigzag chains running parallel to [010].

2-Azido-1-(4-nitro-phen-yl)ethanone.

In the title compound, C(8)H(6)N(4)O(3), the ketone [C-C(=O)-C] and nitro groups are tilted with respect to the benzene ring by 18.92 (6) and 24.11 (15)°, respectively. In the crystal, mol-ecules are linked into inter-woven chains running parallel to the [100] direction by C-H⋯N hydrogen bonds and weak π-π stacking inter-actions, with centroid-centroid separations of 3.897 (3) Å.

Suppression of COX-2/PGE2 levels by carbazole-linked triazoles via modulating methylglyoxal-AGEs and glucose-AGEs - induced ROS/NF-κB signaling in monocytes.

Chronic hyperglycemia favours the formation of advanced glycation end products (AGEs) which are responsible of many diabetic vascular complications. Keeping in view the medicinal properties of the1,2,3-triazole-conjugated analogs, the present study was designed to evaluate the possible effect of carbazole-linked 1,2,3-triazoles 2-16 against glucose- and methylglyoxal-AGEs-induced inflammation in human THP-1 monocytes. In vitro antiglycation, and metabolic assays were used to determine antiglycation, and cytotoxicity activities. DCFH-DA, immunostaining, immunoblotting, and ELISA techniques were employed to study the ROS and levels of proinflammatory mediators in THP-1 monocytes. Among all the synthesized carbazole-linked 1,2,3 triazoles, compounds 2, 7, 8, and 11-16 showed antiglycation activity in glucose- and MGO-modified bovine serum albumin models, whereas parent compound 1 only exhibited activity in glucose-BSA model. The metabolic assay demonstrated the non-toxic profile of compounds 1-2, 11-13, and 15 up to 100 µM concentration in both HepG2 and THP-1 cell lines. We found that compounds 11-13, and 15 attenuated AGEs-induced ROS formation (P < 0.001), and halted NF-ĸB translocation (P < 0.001), likewise standard drugs, PDTC, rutin, and quercetin, in THP-1 monocytes. Among the derivatives, compounds 12, and 13 also suppressed the AGEs-induced elevation of COX-2 (P < 0.001) and PGE2 (P < 0.001). Our data show that the carbazole-linked triazoles 12, and 13 hampering the formation of glycation products, prevent the activation of AGEs-ROS-NF-κB signaling pathway, and limit the proinflammatory COX-2 protein, and PGE2 induction in human THP-1 monocytes. Both these compounds can thus serve as leads for further studies towards the treatment and prevention of diabetic vascular complications.

Indole-linked 1,2,3-triazole derivatives efficiently modulate COX-2 protein and PGE2 levels in human THP-1 monocytes by suppressing AGE-ROS-NF-kß nexus.

AIMS: AGEs augment inflammatory responses by activating inflammatory cascade in monocytes, and hence lead to vascular dysfunction. The current study aims to study a plausible role and mechanism of a new library of indole-tethered 1,2,3-triazoles 2-13 in AGEs-induced inflammation. MATERIAL AND METHODS: Initially, the analogs 2-13 were synthesized by cycloaddition reaction between prop-2-yn-1-yl-2-(1H-indol-3-yl) acetate (1) and azidoacetophenone (1a). In vitro glycation, and metabolic assays were employed to investigate antiglycation and cytotoxicity activities of new indole-triazoles. DCFH-DA, immunostaining, Western blotting, and ELISA techniques were used to study the reactive oxygen species (ROS), and pro-inflammatory mediators levels. KEY FINDINGS: Among all the synthesized indole-triazoles, compounds 1-3, and 9-13, and their precursor molecule 1 were found to be active against AGEs production in in vitro glucose- and methylglyoxal (MGO)-BSA models. Compounds 1-2, and 11-13 were also found to be nontoxic against HEPG2, and THP-1 cells. Our results show that pretreatment of THP-1 monocytes with selected lead compounds 1-2, and 11-13, particularly compounds 12, and 13, reduced glucose- and MGO-derived AGEs-mediated ROS production (P < 0.001), as compared to standards, PDTC, rutin, and quercetin. They also significantly (P < 0.001) suppressed NF-ĸB translocation in THP-1 monocytes. Moreover, compounds 12, and 13 attenuated the AGEs-induced COX-2 protein levels (P < 0.001), and PGE2 production (P < 0.001) in THP-1 monocytes. SIGNIFICANCE: Our data revealed that the indole-triazoles 12, and 13 can significantly attenuate the AGEs-induced proinflammatory COX-2 levels, and associated PGE2 production by suppressing AGE-ROS-NF-Kß nexus in THP-1 monocytes. These compounds can thus serve as leads for further evaluation as treatment to delay early onset of diabetic complications.

Substituted benzenediol Schiff bases as promising new anti-glycation agents.

A feature of diabetes is that the rate of protein glycation and the formation of advanced glycation endproducts (AGEs) increases spontaneously due to the abnormally elevated levels of sugar in the blood. The glycation of proteins is associated with a large number of late diabetic complications (retinopathy, neuropathy, atherosclerosis, end stage renal diseases, rheumatoid arthritis and neurodegenerative diseases). The increase in diabetic complications is a major cause of morbidity and mortality, which has increased significantly in the last two decades. Therefore, there is a considerable recent interest in the identification of lead molecules, which can inhibit the glycation process or slow it down considerably. A new class of anti-glycation agents has been identified, based on the spectrofluorimetric analysis of fluorescent advanced glycation endproducts (AGEs), benzenediol Schiff bases, and their structure-activity relationships have been studied. Some of these compounds have shown a promising anti-glycation potential in vitro.

In vitro α-Glucosidase Inhibition by Non-sugar based Triazoles of Dibenzoazepine, their Structure-Activity Relationship, and Molecular Docking.

BACKGROUND: α-Glucosidase inhibitors (AGIs) have been reported for their clinical potential against postprandial hyperglycemia, which is responsible for the risks associated with diabetes mellitus 2 and cardiovascular diseases (CVDs). Besides, a number of compounds have been reported as potent AGIs, several side effects are associated with them. METHODS: The aim of present work is to explore new and potent molecules as AGIs. Therefore, a library of dibenzoazepine linked triazoles (1-15) was studied for their in vitro α-glucosidase inhibitory activity. The binding modes of potent compounds in the active site of α-glucosidase enzyme were also explored through molecular docking studies. RESULTS AND CONCLUSION: Among the reported triazoles, compounds 3-9, 11, and 13 (IC50 = 6.0 ± 0.03 to 19.8 ± 0.28 µM) were found to be several fold more active than the standard drug acarbose (IC50 = 840 ± 1.73 µM). Compound 5 (IC50 = 6.0 ± 0.03 µM) was the most potent AGIs in the series, about 77- fold more active than acarbose. Therefore, dibenzoazepine linked-triazoles described here can serve as leads for further studies as new non-sugar AGIs.

Quinoxaline derivatives: novel and selective butyrylcholinesterase inhibitors.

Alzheimer's disease (AD) is a progressive brain disorder which occurs due to lower levels of acetylcholine (ACh) neurotransmitters, and results in a gradual decline in memory and other cognitive processes. Acetycholinesterase (AChE) and butyrylcholinesterase (BChE) are considered to be primary regulators of the ACh levels in the brain. Evidence shows that AChE activity decreases in AD, while activity of BChE does not change or even elevate in advanced AD, which suggests a key involvement of BChE in ACh hydrolysis during AD symptoms. Therefore, inhibiting the activity of BChE may be an effective way to control AD associated disorders. In this regard, a series of quinoxaline derivatives 1-17 was synthesized and biologically evaluated against cholinesterases (AChE and BChE) and as well as against α- chymotrypsin and urease. The compounds 1-17 were found to be selective inhibitors for BChE, as no activity was found against other enzymes. Among the series, compounds 6 (IC50 = 7.7 ± 1.0 µM) and 7 (IC50 = 9.7 ± 0.9 µM) were found to be the most active inhibitors against BChE. Their IC50 values are comparable to the standard, galantamine (IC50 = 6.6 ± 0.38 µM). Their considerable BChE inhibitory activity makes them selective candidates for the development of BChE inhibitors. Structure-activity relationship (SAR) of this new class of selective BChE inhibitors has been discussed.

Metronidazole esters: a new class of antiglycation agents.

A series of metronidazole ester derivatives 1-34 has been synthesized with the aim of developing new leads with antiglycation activity. The in vitro evaluation of antiglycation potential of 1-34 showed that the ester derivatives 28, 16, and 3 have IC(50) values 218.97 ± 2.5, 245.3 ± 5.1, and 278.6 ± 0.8 µM, respectively, comparable to the standard agent, rutin (IC(50) = 294.5 ± 1.50 µM). The study identifies a new class of potent antiglycation agents. A structure-activity relationship has also been evaluated. All the compounds were characterized by using spectroscopic techniques, including (1)H NMR, IR, and EI-MS.

Synthesis of a unique isoindoline/tetrahydroisoquinoline-based tricyclic sultam library utilizing a Heck-aza-Michael strategy.

The synthesis of a unique isoindoline- and tetrahydroisoquinoline (THIQ)-containing tricyclic sultam library, utilizing a Heck-aza-Michael (HaM) strategy is reported. Both isoindoline and THIQ rings are installed through a Heck reaction on a vinylsulfonamide, followed by one-pot deprotection and intramolecular aza-Michael reaction. Subsequent cyclization with either paraformaldehyde condensation or 1,1'-carbonyldiimidazole coupling generates a variety of tricyclic sultams. Overall, a 160-member library of these sultams, together with their isoindolines/THIQ and secondary sulfonamides precursors, were constructed using this strategy.

Synthesis and antiglycation activity of kaempferol-3-O-rutinoside (nicotiflorin).

Kaempferol-3-O-α-L-rhamanopyranosyl-(1'''-6'')-ß-D-glucopyranoside (1) (Nicotiflorin or kaempferol-3-O-rutinoside), isolated from the aerial parts of Osyris wightiana Wall. ex Wight, exhibited a potent antiglycation activity in vitro. A short and efficient route to kaempferol-3-O-rutinoside (1) is also described in this paper. To study the structure-activity relationship, few other derivatives of kaempferol were also evaluated for their antiglycation activity. Moreover the cytotoxicity analysis was also performed for these compounds. The Structure-Activity Relationship (SAR) studies showed that sugar derivatives of kaempferol possess a promising antiglycation activity.