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1.
Bioorg Chem ; 119: 105506, 2022 02.
Article in English | MEDLINE | ID: mdl-34896920

ABSTRACT

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.


Subject(s)
Clioquinol/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Molecular Docking Simulation , alpha-Glucosidases/metabolism , Cells, Cultured , Clioquinol/chemical synthesis , Clioquinol/chemistry , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Kinetics , Molecular Structure , Structure-Activity Relationship
2.
Bioorg Chem ; 127: 105944, 2022 10.
Article in English | MEDLINE | ID: mdl-35905644

ABSTRACT

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 IC50 = 5.5 ± 0.3-124.5 ± 0.4 µM against butyrylcholinesterase enzyme. Among them, compound 15 was a potent BChE inhibitor (IC50 = 5.5 ± 0.3 µM), as compared to the standard drug galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Active compounds were further subjected to kinetic, and molecular docking studies to predict their modes of inhibition, and interactions with the receptor (BChE), respectively. Enzyme kinetics studies showed that compounds 9 (IC50 = 25.3 ± 0.5 µM), and 14 (IC50 = 23.9 ± 0.5 µM) were non-competitive inhibitors, while compound 15 exhibited a competitive inhibition. In addition, these compounds were found to be non-cytotoxic against human fibroblast (BJ) cell line, except 9 (IC50 = 17.1 ± 1.0 µM), and 10 (IC50 = 18.4 ± 0.3 µM). Inhibition of cholinesterases is an important approach for development of drugs against Alzheimer's disease, and thus discoveries presented here deserve further investigation.


Subject(s)
Berberis , Butyrylcholinesterase , Acetylcholinesterase/metabolism , Berberis/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 40: 127979, 2021 05 15.
Article in English | MEDLINE | ID: mdl-33766763

ABSTRACT

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.


Subject(s)
Dibenzazepines/chemistry , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemistry , Isoxazoles/chemistry , 3T3 Cells , Animals , Cycloaddition Reaction , Dibenzazepines/chemical synthesis , Dibenzazepines/toxicity , Enzyme Assays , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/toxicity , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/toxicity , Isoxazoles/chemical synthesis , Isoxazoles/toxicity , Kinetics , Mice , Molecular Docking Simulation , Molecular Structure , Oligo-1,6-Glucosidase/metabolism , Protein Binding , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae Proteins/metabolism , Structure-Activity Relationship
4.
Bioorg Chem ; 106: 104499, 2021 01.
Article in English | MEDLINE | ID: mdl-33288319

ABSTRACT

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.


Subject(s)
Celecoxib/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Molecular Docking Simulation , alpha-Glucosidases/metabolism , Celecoxib/chemical synthesis , Celecoxib/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship
5.
Bioorg Med Chem ; 27(18): 4030-4040, 2019 09 15.
Article in English | MEDLINE | ID: mdl-31378596

ABSTRACT

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.


Subject(s)
Benzamides/therapeutic use , Cholinesterase Inhibitors/therapeutic use , Molecular Docking Simulation/methods , Benzamides/pharmacology , Cholinesterase Inhibitors/pharmacology , Humans , Kinetics , Molecular Structure , Structure-Activity Relationship
6.
Pak J Pharm Sci ; 32(3 Special): 1285-1291, 2019 May.
Article in English | MEDLINE | ID: mdl-31551205

ABSTRACT

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, 1H-NMR, ESI-MS and CHNS techniques. It was observed that BPBP acted as a bidentate ligand. The metal to ligand stoichiometry was 1:3 for all the synthesized complexes. The complexes had octahedral structure with C3 symmetry. The antioxidant activity was evaluated using free radical scavenging assay. BPBP showed insignificant antioxidant and lipoxygenase activities while its transition metal complexes showed promising activities. Antioxidant activity of Fe and Co-complexes was found significantly higher than the reference drug used in this study.


Subject(s)
Antioxidants/chemistry , Antioxidants/pharmacology , Coordination Complexes/chemistry , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/pharmacology , 2,2'-Dipyridyl/chemistry , Antioxidants/chemical synthesis , Cobalt/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , Drug Evaluation, Preclinical , Iron/chemistry , Ligands , Lipoxygenase Inhibitors/chemical synthesis , Magnetic Resonance Spectroscopy , Microwaves , Molecular Structure , Ruthenium/chemistry
7.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1253-1259, 2019 May.
Article in English | MEDLINE | ID: mdl-31303598

ABSTRACT

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.


Subject(s)
Arachidonate 5-Lipoxygenase/chemistry , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Oxamic Acid/analogs & derivatives , Amines/chemistry , Arachidonate 5-Lipoxygenase/metabolism , Chlorides/chemistry , Drug Evaluation, Preclinical , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Oxalates/chemistry , Oxamic Acid/chemistry , Protein Conformation , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship
8.
Bioorg Chem ; 74: 72-81, 2017 10.
Article in English | MEDLINE | ID: mdl-28756277

ABSTRACT

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.


Subject(s)
Carbazoles/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Triazoles/pharmacology , alpha-Glucosidases/metabolism , 3T3 Cells , Animals , Carbazoles/chemistry , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Mice , Molecular Structure , Structure-Activity Relationship , Triazoles/chemistry
9.
Med Chem ; 19(10): 996-1001, 2023.
Article in English | MEDLINE | ID: mdl-37005533

ABSTRACT

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.


Subject(s)
Aromatase Inhibitors , Breast Neoplasms , Pregnancy , Female , Humans , Aromatase Inhibitors/pharmacology , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/therapeutic use , Aromatase/chemistry , Aromatase/metabolism , Aromatase/therapeutic use , Kinetics , Placenta/metabolism , Breast Neoplasms/drug therapy , Estrogens/therapeutic use , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use
10.
Life Sci ; 291: 120282, 2022 Feb 15.
Article in English | MEDLINE | ID: mdl-34990649

ABSTRACT

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.


Subject(s)
Glycation End Products, Advanced/metabolism , Indoles/pharmacology , Triazoles/pharmacology , Cyclooxygenase 2/metabolism , Cytokines/metabolism , Dinoprostone/metabolism , Glycation End Products, Advanced/drug effects , Humans , Indoles/chemistry , Inflammation/metabolism , Inflammation Mediators/metabolism , Monocytes/metabolism , NF-kappa B/metabolism , Reactive Oxygen Species/metabolism , THP-1 Cells , Triazoles/chemistry
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