Drugs Against Neurodegenerative Diseases: Design and Synthesis of 6‐Amino–substituted Imidazo[1,2‐<i>b</i>]pyridazines as Acetylcholinesterase Inhibitors

Sridhar, P.; Ram, B.; Sivakumar, A.; Reddy, Sabbasani Rajasekhara

doi:10.1002/slct.201601353

Cited by 24 publications

(17 citation statements)

References 46 publications

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“…In the pathogenesis of numerous diseases, free radicals are playing a key role in their development . In the mechanism, by oxidizing essential thiol (–SH) groups, H 2 O 2 destroys the cell's functional enzyme activities directly and rapidly passing cell membranes then reacts with Fe 2+ and Cu 2+ ions to form hydroxyl radicals that are causing toxic effects .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Molecular Drug Efficacy of Indoline‐based Dihydroxy‐thiocarbamides: Inflammation Regulatory Property Unveiled over COX‐2 Inhibition, Molecular Docking, and Cytotoxicity Prospects

M¹,

Dhayabaran²

2018

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).In this study, substituted indoline-based dihydroxy-carbamides (5a-i) were synthesized and evaluated as the cyclooxygenase-2 (COX-2) inhibitors to testify their inflammatory regulations through COX-2 inhibition. Enzyme-linked immunosorbent assay-based competitive (COX-2) inhibition (in vitro) followed by a molecular docking study (in silico) was executed to ensure the mode of interaction between 5a-i and COX-2. Apart from COX-2 inhibition studies, free-radical scavenging ability (H 2 O 2 estimation method) and the human red blood cell membrane protection (in vitro anti-inflammatory) capability of the compounds 5a-i assessment were also evaluated. Excellent antimicrobial and anticancer activity exhibited by thiocarbamide substituted compounds (5a-d) than carbamide (5e-i). In molecular docking studies, the obtained binding affinity values of 5a-i indicated the therapeutic selectivity on COX-2 (PDB ID: 1CX2) over COX-1 (PDB ID: 1EQG). Established inhibitory constant (ki) values were found as low as in nanomolar/picomolar against COX-2. Reliable COX-2 inhibition of 78-92% and IC 50 0.002-1.28 μM were obtained. Human red blood cell membrane was found to be effectively stabilized/protected by 5a-i up to 98%. Excellent antioxidant property (average radical scavenging 92%) and structure-activity relationship predictions confirmed the druggability potentials of 5a-i as effective, future anti-inflammatory drugs. The cytotoxicity of the compounds was also unveiled by MTT assay using MCF-7 (human breast cancer), SW620 (human colon cancer), G361 (human skin cancer), human breast normal cell lines (MCF-10), and cell lines.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Molecular Drug Efficacy of Indoline‐based Dihydroxy‐thiocarbamides: Inflammation Regulatory Property Unveiled over COX‐2 Inhibition, Molecular Docking, and Cytotoxicity Prospects

M¹,

Dhayabaran²

2018

Journal of Heterocyclic Chem

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“…Crystal structures of the amino‐terminal SH2 domain of the p85 alpha subunit of phosphatidylinositol PI3‐Kinase [Protein Data Bank (PDB) ID: 2IUG] were retrieved from PDB (source: http://www.rcsb.org/pdb) . AutoDock 4.2.6 and AutoDock Tools 1.5.6 and the ArgusLab version 4.0.1 were used for the docking studies . The docked poses with lowest binding energy, hydrogen bonding, and non‐covalent bonding (π–π interaction and π–cation interaction) details were recorded and validated.…”

Section: Methodsmentioning

confidence: 99%

Molecular Substantiation and Drug Efficacy of Relatively High Molecular Weight S‐BINOLs; Appraised as Breast Cancer Medication and PI3Kinase Inhibitors

Muralidharan

Sivakumar

Iyer

2018

Journal of Heterocyclic Chem

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Relatively high molecular weight S‐BINOLs with substituted functional groups were synthesized, and structures were elucidated by FTIR, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and HRMS. As a preliminary step, the compounds were docked into the active site of phosphoinositide3‐kinase (PI3Kinase) (Protein Data Bank ID: 2IUG) that is a crucial regulator of apoptosis or programmed cell death. To ensure the PI3Kinase inhibition, because it was predicted as the most suitable bioactivity of these compounds, a competitive ELISA PI3Kinase inhibition study was carried out. Compounds 3, 4a, 4b, and 6 were assessed for cytotoxicity/antiproliferative effects on MCF‐7 (breast cancer) and HCT116 (colon cancer) cell lines. In the docking studies, excellent binding affinities of 3, 4a, 4b, and 6 (−11.36, −14.52, −14.86, and −21.76 kcal/mol, respectively) and the inhibitory constants (ki) (4.75 nM, 81.64 pM, 78.23 pM, and 14.24 pM, respectively) encouraged us to carry out anticancer studies further. Excellent inhibitory values were obtained in the range of 82–90% relative activity and IC50 range of 5–12 nM. In the cytotoxicity, the relative inhibition activity was remarkably found high in MCF‐7 cell lines as 89.14% (6), 82.18% (4b), 80.46% (3), and 74.78% (4a) with the IC50 range of 0.02–0.18 μM. No compounds were found inactive for the proposed activity in this study. The Structure Activity Relationship studies prove that compounds 3, 4a, 4b, and 6 are specific PI3Kinase inhibitors with the competence to cure breast cancers.

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“…Autodock 4.2.6 and Autodock Tools (ADT) 1.5.6. were used for the docking studies . Their 3D atomic co‐ordinates of N‐substituted hydroxynaphthalene imino‐oxindole derivatives ( 5a–g ) were created using ACD/Labs— Chemsketch 12.0 software.…”

Section: Methodsmentioning

confidence: 99%

N‐substituted hydroxynaphthalene imino‐oxindole derivatives as new class of PI3‐kinase inhibitor and breast cancer drug: Molecular validation and structure–activity relationship studies

Kumar¹,

Dhayabaran²

2017

Chem Biol Drug Des

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N-substituted hydroxynaphthalene imino-oxindole derivatives (5a-g) were emerged as the inhibitors of the phosphoinositide 3-kinase (PI3K), which is a crucial regulator of apoptosis or programmed cell death. Electron donor-/acceptor-substituted indoleimine (5a-g) was achieved, and the structures were elucidated by FTIR, 1H NMR, 13C NMR and HRMS. Inhibition potency of PI3Ks was assessed by competitive ELISA. Subsequently, an anticancer activity against breast cancer (MCF-7) cell lines was evaluated. In both activities, compounds 5c, 5d and 5f showed most potent activities. Percentage inhibition for anticancer activity was 78.22 ± 1.02 (5c) and 78.98 ± 1.08 (5f), and the IC 50 was 2.02 ± 0.92 μm (5c) and 1.98 ± 0.18 μm (5f). Compounds 5a and 5g were found inactive for both activities, and rest all showed a moderate activity. To get more insight into the binding mode and inhibitor binding affinity, 5a-g were docked into the active site of PI3Ks p110α (PDB ID: 2ENQ).Results suggested that the hydrophobic interactions in the binding pockets of PI3Ks conquered affinity of the most favourable binding ligands (5c and 5f: inhibitory constant (k i ) = 102. 4 and 128.23 nm). The SAR studies demonstrate the efficiency of 5a-g as the PI3Ks precise inhibitors with the impending to treat various cancers. K E Y W O R D Santicancer studies, drug designing, molecular docking, N-substituted indole-imine derivatives, PI3-kinase

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Drugs Against Neurodegenerative Diseases: Design and Synthesis of 6‐Amino–substituted Imidazo[1,2‐b]pyridazines as Acetylcholinesterase Inhibitors

Cited by 24 publications

References 46 publications

Synthesis and Molecular Drug Efficacy of Indoline‐based Dihydroxy‐thiocarbamides: Inflammation Regulatory Property Unveiled over COX‐2 Inhibition, Molecular Docking, and Cytotoxicity Prospects

Synthesis and Molecular Drug Efficacy of Indoline‐based Dihydroxy‐thiocarbamides: Inflammation Regulatory Property Unveiled over COX‐2 Inhibition, Molecular Docking, and Cytotoxicity Prospects

Molecular Substantiation and Drug Efficacy of Relatively High Molecular Weight S‐BINOLs; Appraised as Breast Cancer Medication and PI3Kinase Inhibitors

N‐substituted hydroxynaphthalene imino‐oxindole derivatives as new class of PI3‐kinase inhibitor and breast cancer drug: Molecular validation and structure–activity relationship studies

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