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Tetrahydrocarbazoles are important class of heterocycles that exhibit numerous biological properties. They are also found in several natural products. In the present study, Fischer indolization of L-menthone was investigated for diastereoselectivity using different reaction conditions. No appreciable diastereoselectivity was observed for the acids used except CuBr and boric acid at varying temperatures, where satisfactory results were obtained. In addition, a small library of new (2R,4aS)-2,3,4,4a-tetrahydro-1H-carbazole analogs was reported and structurally characterized using spectroscopic techniques herein. Additionally, the compounds were evaluated against different biological activities, such as carbonic anhydrase inhibitory, immunomodulatory, and anticancer activities and did not show any activity. As the synthesized library was found safe when tested against cytotoxicity in normal cell line, it will be explored for other biological activities in near future to identify its biological outcome.

INTRODUCTION:: Breast cancer is the most common cancer affecting women worldwide, including Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer, which is developed due to the over-production of estrogen (the main hormone in breast cancer). METHOD:: The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as a target for the treatment of breast cancer. During the current study, biochemical, computational, and STD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3-butene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 µM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 = 0.0147 ± 1.45 µM), anastrozole (IC50 = 0.0094 ± 0.91 µM), and exemestane (IC50 = 0.2 ± 0.032 µM). Kinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively. RESULT:: Docking studies on all active compounds indicated their binding adjacent to the heme group and interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme. CONCLUSION:: STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be non-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified new aromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research. result: A series of phenyl-3-butene-2-one derivatives 1-9were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50= 22.6 - 42.7 µM), as compared to standard aromatase inhibitory drugs letrozole (IC50 = 0.0147 ± 1.45 nM), and anastrozole (IC50 = 9.4 ± 0.91 nM). Kinetic studies on two moderate inhibitors,4 and 8, revealed a competitive and mixed type of inhibition, respectively. Docking studies on all active compounds indicated their binding adjacent to the heme group and interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interaction of these ligands with aromatase. STD-NMR based epitope mapping indicated close proximity of the alky chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be non-cytotoxic against human fibroblast cells (BJ cells). conclusion: Thus, the current study has identified new aromatase inhibitors (compounds 4, and 8), and these could be further considered as anti-cancer agents after in-vivo studies.

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.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.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 PGEOur data revealed that the indole-triazoles 12, and 13 can significantly attenuate the AGEs-induced proinflammatory COX-2 levels, and associated PGE

Seven known isoquinoline alkaloids 1-7 were isolated from the root extracts of Berberis parkeriana Schneid. Nine new derivatives 8-16 of one of the isolated compounds, jatrorrhizine (7), were synthesized. All the isolated as well as derivatized compounds were evaluated for their in-vitro acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity. Functionalized compounds selectively exhibited a potent-to-moderate activity with IC

Diabetes mellitus is a chronic metabolic disorder, with increasing prevalence and long-term complications. The aim of this study was to identify α-glucosidase inhibitory compounds with potential anti-hyperglycemic activity. For this purpose, a series of new clioquinol derivatives 2a-11a was synthesized, and characterized by various spectroscopic techniques. The enzyme inhibitory activities of the resulting derivatives were assessed using an in-vitro mechanism-based assay. All the tested compounds 2a-11a of the series showed a significant α-glucosidase inhibition with IC50 values 43.86 − 325.81 µM, as compared to the standard drug acarbose 1C50: 875.75 ± 2.08 µM. Among them, compounds 4a, 5a, 10a, and 11a showed IC50 values of 105.51 ± 2.41, 119.24 ± 2.37, 99.15± 2.06, and 43.86 ± 2.71 µM, respectively. Kinetic study of the active analogues showed competitive, non-competitive, and mixed-type inhibitions. Furthermore, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of α-glucosidase enzyme. The results indicate that these compounds have the potential to be further studied as new anti-diabetic agents.

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 ± 0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ± 0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ± 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.

Celebrex (1), commonly used as an anti-inflammatory drug, was functionalized (compounds 2–9) to identify new α-glucosidase inhibitors. Initially, all the synthesized derivatives were evaluated for anti-inflammatory activity but none was found to be active. Subsequently a random biological screening was carried out. Interestingly many of them were found to be potent α-glucosidase inhibitors in vitro. All the structures of synthesized derivatives were deduced through 1H NMR, FAB-MS, HR-MS, FT-IR analysis. The single-crystal X-ray structures of compounds 1, and 5 further confirmed the assigned structures. Compounds exhibited a potent α-glucosidase inhibitory activity (IC50 = 92.32 ± 1.530–445.20 ± 1.04 µM) against tested standard acarbose (IC50 = 875.75 ± 2.08 µM), except compounds 2 and 4, which appeared as inactive. Among them, compound 9 (IC50 = 92.32 ± 1.530 µM) was the most potent inhibitor of α-glucosidase enzyme. Molecular docking studies revealed that compounds 6, and 9 interacted with the key amino acid residues of α-glucosidase via H-bonding, and π-π stacking interactions. α-Glucosidase is a key target for the anti-diabetic drug development, and its inhibitors are known to exert anti hyperglycemic effect and help in lowering of post-prandial blood glucose levels.

Dibenzoazepine represents an important class of heterocycles, exhibiting potent antidepressant and anticonvulsant activities. Beside, various modifications on this nucleus, amide analogs at N -5 position showed potent antidepressant activities. A previously reported method for the synthesis of benzamide analogs of dibenzoazepine use hazardous and toxic solvents. Herein, we report a new, efficient and solvent-free green method for the synthesis of dibenzoazepine benzamides (6-21).

Halophytes, distributed from coastal regions to inland deserts have traditionally been used for medicinal and nutritional purposes. Living in sub-optimal conditions, these plants synthesize stress associated bioactive molecules, which are still remain largely unexplored. In search of natural antioxidant sources, antioxidant capacity (AC) and total phenolic content (TPC) of 100 medicinal plants (halophytes vs non-halophytes), commonly used as herbal teas, were investigated. Nutrients and phytochemical composition, especially phenolic metabolites in selected medicinal plants with higher AC were also determined. Most of the medicinal plants analysed for the first time showed considerable AC. In general, halophytes displayed higher AC and TPC than non-halophytes. High correlation indicated a major contribution of TPC in AC of these plants. Five medicinal halophytes i.e., Thespesia populneoides , Salvadora persica , Ipomoea pes-caprae , Suaeda fruticosa , and Pluchea lanceolata displayed significantly higher AC than synthetic antioxidants (BHT and BHA). Presence of bioactive phytochemicals including phenols (42.3–63.9 mg GAE g − 1 ), flavonoids (12.3–37.1 mg QE g − 1 ), tannins (8.7–20 mg TAE g − 1 ), proanthocyanidins (15.8–22.4 mg CE g − 1 ), carotenoids (0.07–0.84 mg g − 1 ), alkaloids (0.64–1.1 mg g − 1 ), and saponins (11.2–28.4 mg DAE g − 1 ) reflected therapeutic benefits of these plants. HPLC analyses showed that the hydrolysed extracts contained chlorogenic acid, gallic acid, catechin, and quercetin as abundant phenolic metabolites which may be responsible for higher AC. These plants were also found to contain suitable amounts of proteins (8.5–17%), carbohydrates (2.6–11.4%), fibre (31.6–41.2%), and minerals (2.1–9.7%) showing their nutritional potential that has already been exploited by rural communities. The present study highlights the potential of medicinal halophytes as a source of natural antioxidants, valuable phytochemicals, and essential nutrients for pharmaceutical, nutraceutical, and chemical industries.

Synthesis of new antioxidants and enzyme inhibitors is an active area of research in pharmaceutical sciences. This can be used for development of new active product ingredients which can prevent body from different diseases. This study comprises of preparation of transition metal complexes using 4-(4-bromophenyl)-2,2'-bipyridine (BPBP) and their screening for antioxidant and lipoxygenase inhibition properties. 4-(4-bromophenyl)-[2,2'-bipyridine]-6-carboxylic acid was used as starting material and its decarboxylation resulted in BPBP. Decarboxylation by conventional heating method was compared with microwave decarboxylation method. Selected metal complexes of the ligand were synthesized with Ruthenium (II), Iron (II) and Cobalt (II) ions. The complexes were characterized using UV, IR

In this study, a range of oxamide ligands were synthesized by the reaction of amines with oxalyl chloride in basic medium. Spectroscopic and analytical techniques such as IR, 1H-NMR and ESI-MS techniques were used for characterization of the synthesized oxamides. The synthesized oxamides were screened for Lipoxygenase inhibition. Biological screening revealed that the oxamides possessed good lipoxygenase inhibition activities, whereas, the unsubstituted oxamide did not show any distinct lipoxygenase inhibition activity. Molecular docking studies of the oxamides were also carried out for lipoxygenase inhibition. The results obtained from molecular docking were well correlated with the empirical data.

Carbazole analogs 3 and 4 and a new library of bicarbazole-linked triazoles 6–11 were prepared via new synthetic methodology. Metal-catalyzed oxidative coupling reaction was utilized for the synthesis of bicarbazole acetylene 4 and different metals (Zn+2, Co+2, Fe+3, Ni+2, Cu+2, Mn+2) as catalyst were screened. Only Fe-catalyzed reaction was found to be excellent and gave homocoupled product 4. Cu-catalyzed 1,3-dipolar cycloaddition was also utilized to install triazole moiety for the synthesis of hybrid molecules 6–11. Based on reported anti-inflammatory activity of carbazole and triazole scaffolds, all compounds were screened for their reactive oxygen species (ROS) inhibitory potential. Results from these studies revealed triazole 9 as most active compound (IC50 value of 7.6 ± 0.1 µg/mL on human whole blood and 2.7 ± 0.09 µg/mL on isolated neutrophils) using ibuprofen as a standard. Therefore, class described herein can serve as attractive structural element for further studies on ROS inhibition.

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.

The present study describes the regioselective synthesis of novel 2,3,4,4a-tetrahydro-1H-carbazoles (syn-2(a–q) and anti-3(a–b)) from L-menthone via Fischer indole synthesis. The reaction between L-menthone and different substituted phenyl hydrazines, carried out in acetic acid as catalyst and solvent, yielded a mixture of corresponding 2,3,4,4a-tetrahydro-1H-carbazole diastereomers, instead of the expected indoles. These were characterized by different spectroscopic and single-crystal X-ray diffraction techniques. The isolated single diastereoisomers were further evaluated for inhibitory activities against various enzymes such as cholinesterases, xanthine oxidase, α-chymotrypsin, urease, phosphodiesterase and carbonic anhydrase-II activity, as well as against DPPH radical scavenging and anti-cancer activity against PC-3 cell line. The 2,3,4,4a-tetrahydro-1H-carbazoles show promising inhibitory activities only against acetyl- and butyrylcholinesterase. Moreover, kinetic analyses were carried out for the study of mechanism of inhibition of the active compounds.

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.

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.

Suaeda fruticosa Forssk is a leaf succulent obligate halophyte that produces numerous seeds under saline conditions. Seeds are a good source of high quality edible oil and leaves are capable of removing substantial amount of salt from the saline soil besides many other economic usages. Little is known about the biochemical basis of salt tolerance in this species. We studied some biochemical responses of S. fruticosa to different exog- enous treatments under non-saline (0 mM), moderate (300 mM) or high (600 mM) NaCl levels. Eight-week- old seedlings were sprayed twice a week with distilled water, hydrogen peroxide (H2O2, 100 lM), glycine betaine (GB, 10 mM), or ascorbic acid (AsA, 20 mM) for 30 days. At moderate (300 mM) NaCl, leaf Na ? ,C a 2? and osmolality increased, along with unchanged ROS and antioxidant enzyme activities, possibly causing a better plant growth. Plants grew slowly at 600 mM NaCl to avoid leaf Na ? buildup relative to those at 300 mM NaCl. Exogenous application of distilled water and H2O2 improved ROS scavenging mechanisms, although growth was unaffected. ASA and GB alleviated salt-induced growth inhibition at 600 mM NaCl through enhancing the antioxidant defense system and osmotic and ion homeo- stasis, respectively.

The present study describes the regioselective synthesis of novel 2,3,4,4a-tetrahydro-1H-carbazoles (syn-2(a–q) and anti-3(a–b)) from L-menthone via Fischer indole synthesis. The reaction between L-menthone and different substituted phenyl hydrazines, carried out in acetic acid as catalyst and solvent, yielded a mixture of corresponding 2,3,4,4a-tetrahydro-1H-carbazole diastereomers, instead of the expected indoles. These were characterized by different spectroscopic and single-crystal X-ray diffraction techniques. The isolated single diastereoisomers were further evaluated for inhibitory activities against various enzymes such as cholinesterases, xanthine oxidase, α-chymotrypsin, urease, phosphodiesterase and carbonic anhydrase-II activity, as well as against DPPH radical scavenging and anti-cancer activity against PC-3 cell line. The 2,3,4,4a-tetrahydro-1H-carbazoles show promising inhibitory activities only against acetyl- and butyrylcholinesterase. Moreover, kinetic analyses were carried out for the study of mechanism of inhibition of the active compounds.

The asymmetric unit of the title compound, C17H13N, contains two independent butterfly-shaped molecules. The seven-membered azepine rings both adopt a boat conformation. The dihedral angles between the benzene rings in the two molecules are 46.95 (11) and 52.21 (11)°.