Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity

Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayedantiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p<0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p<0.01), and the number of rats that maintained sinus rhythm for more than 20 minutes (p<0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50=59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.

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In Vivo and in Vitro Structure-Activity Relationships and Structural Conformation of Kisspeptin-10-Related Peptides

Molecular Pharmacology ◽

10.1124/mol.108.053751 ◽

2009 ◽

Vol 76 (1) ◽

pp. 58-67 ◽

Cited By ~ 41

Author(s):

Ester Gutiérrez-Pascual ◽

Jérôme Leprince ◽

Antonio J. Martínez-Fuentes ◽

Isabelle Ségalas-Milazzo ◽

Rafael Pineda ◽

...

Keyword(s):

Structure Activity Relationships ◽

Structural Conformation ◽

Structure Activity

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Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands

Molecules ◽

10.3390/molecules24081463 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1463

Author(s):

Katherine N. Schlasner ◽

Mark D. Ericson ◽

Skye R. Doering ◽

Katie T. Freeman ◽

Mary Weinrich ◽

...

Keyword(s):

Food Intake ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Biological Pathways ◽

Melanocortin Receptors ◽

Lead Compounds ◽

Structure Activity ◽

Selective Ligands ◽

Selective Agonists

The five melanocortin receptors (MC1R–MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.

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Discovery and preliminary structure–activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2012.11.072 ◽

2013 ◽

Vol 23 (2) ◽

pp. 452-454 ◽

Cited By ~ 16

Author(s):

Lydia P.P. Liew ◽

Marcel Kaiser ◽

Brent R. Copp

Keyword(s):

Structure Activity Relationship ◽

Activity Relationship ◽

Lead Compounds ◽

Relationship Analysis ◽

Structure Activity

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Synthesis of Antimicrobial N-Phthaloyl-alanyl-derived Amidophosphates and Triazoles

Zeitschrift für Naturforschung B ◽

10.1515/znb-2009-0911 ◽

2009 ◽

Vol 64 (9) ◽

pp. 1057-1064 ◽

Cited By ~ 10

Author(s):

Wafaa M. Abdou ◽

Neven A. Ganoub ◽

Eman Sabry

Keyword(s):

Benzoyl Peroxide ◽

Structure Activity Relationship ◽

Structural Features ◽

Activity Relationship ◽

Lead Compounds ◽

Structure Activity ◽

Trialkyl Phosphites

N-Phthaloyl-alanylazide reacts smoothly with trialkyl phosphites producing the corresponding α- aminophosphates. With dialkyl hydrogenphosphonates in the presence of benzoyl peroxide, amidophosphates were the isolated products whereas the oxoaziridin-1-yl-phosphonic diamide was preferentially provided from the reaction of the azide with tris(dimethylamino)phosphine. The azide was also allowed to react with α-keto-, α-ethoxycarbonyl- and α-cyanomethylenetriphenylphosphorane to give the corresponding linear disubstituted 1,2,3-triazoles. Screening results of antibiotic potency for the products were discussed in terms of structure-activity relationship (SAR), and an attempt was made to define the structural features for lead compounds.

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Quantitative Structure-Activity Relationship/Quantitative Structure-Toxicity Relationship (QSAR/QSTR) Modeling as Tools for Assessing Effects and Predicting Risks of Transformation Products of Emerging Contaminants

Transformation Products of Emerging Contaminants in the Environment ◽

10.1002/9781118339558.ch29 ◽

2014 ◽

pp. 859-876

Author(s):

Lars Carlsen ◽

Bulat Kenessov

Keyword(s):

Emerging Contaminants ◽

Transformation Products ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Quantitative Structure ◽

Structure Activity ◽

Structure Toxicity Relationship ◽

Toxicity Relationship

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THE ALKALOIDS OF FUMARIACEOUS PLANTS: XXXVI. CORYDALIS THALICTRIFOLIA FRANCH. AND THE CONSTITUTION OF A NEW ALKALOID, THALICTRIFOLINE

Canadian Journal of Research ◽

10.1139/cjr43b-013 ◽

1943 ◽

Vol 21b (6) ◽

pp. 111-116 ◽

Cited By ~ 10

Author(s):

Richard H. F. Manske

Keyword(s):

Methylenedioxy Group ◽

Methoxy Groups

Corydalis thalictrifolia Franch. has yielded eight alkaloids, four of which, namely, protopine, stylopine, l-corypalmine, and adlumidine, are known bases. The remaining four, thalictrifoline (alkaloid F58) (C21H23O4N), and its dehydro-base, alkaloid F59 (C20H23O4N), and alkaloid F60 (C20H21O3N), are new. The constitution of thalictrifoline has been elucidated. It is corydaline in which the 9:10-methoxy-groups have been replaced by a methylenedioxy-group.

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Promising Fungicides from Allelochemicals: Synthesis of Umbelliferone Derivatives and Their Structure–Activity Relationships

Molecules ◽

10.3390/molecules23113002 ◽

2018 ◽

Vol 23 (11) ◽

pp. 3002 ◽

Cited By ~ 2

Author(s):

Le Pan ◽

Dongyu Lei ◽

Lu Jin ◽

Yuan He ◽

Qingqing Yang

Keyword(s):

Natural Products ◽

Antifungal Activity ◽

Primary Structure ◽

Fungicidal Activity ◽

Inhibitory Rate ◽

Lead Compounds ◽

Parasitic Fungi ◽

Structure Activity ◽

Plant Parasitic ◽

Plant Parasitic Fungi

Umbelliferone was discovered to be an important allelochemical in our previous study, but the contribution of its activity and structure has not yet been revealed. In this study, a series of analogues were synthesized to determine the skeleton of umbelliferone and examine its fungicidal activity. Furthermore, targeted modifications were conducted with three plant parasitic fungi to examine the lead compounds. Among those tested, compounds 2f and 10 were found to show excellent antifungal activity with an inhibitory rate over 80% at 100 ug/mL. The study proves that umbelliferone can be a promising skeleton for fungicides discovery. In addition, the primary structure–activity relationship provides a good guidance for the discovery of novel fungicides based on natural products in the future.

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A medicinal chemist’s perspective towards structure activity relationship of heterocycle based anti-cancer agents

Current Topics in Medicinal Chemistry ◽

10.2174/1568026622666220111142617 ◽

2022 ◽

Vol 22 ◽

Author(s):

Bhupender Nehra ◽

Bijo Mathew ◽

Pooja A Chawla

Keyword(s):

Medicinal Chemistry ◽

High Stress ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Lead Compounds ◽

Structure Activity ◽

Recent Advances ◽

Wide Range ◽

Heterocyclic Derivatives ◽

Relationship Of

Aim: To describe structure activity relationship of heterocyclic derivatives with multi-targeted anticancer activity. Objectives: With the following goals in mind, this review tries to describe significant recent advances in the medicinal chemistry of heterocycle-based compounds: (1) To shed light on recent literature focused on heterocyclic derivatives' anticancer potential; (2) To discuss recent advances in the medicinal chemistry of heterocyclic derivatives, as well as their biological implications for cancer eradication; (3) To summarise the comprehensive correlation of structure activity relationship (SAR) with pharmacological outcomes in cancer therapy. Background: Cancer remains one of the major serious health issues devastating the world today. Cancer is a complex disease in which improperly altered cells proliferate at an uncontrolled, rapid, and severe rate. Variables such as poor dietary habits, high stress, age, and smoking, can all contribute to the development of cancer. Cancer can affect almost any organ or tissue, although the brain, breast, liver, and colon are the most frequently affected organs. From several years, surgical operations and irradiation are in use along with chemotherapy as a primary treatment of cancer but still effective treatment of cancer remains a huge challenge. Chemotherapy is now one of the most effective strategies to eradicate cancer, although it has been shown to have a number of cytotoxic and unfavourable effects on normal cells. Despite all of these cancer treatments, there are several other targets for anticancer drugs. Cancer can be effectively eradicated by focusing on these targets, which include both cell-specific and receptor-specific targets such as tyrosine kinase receptors (TKIs). Heterocyclic scaffolds also have a variety of applications in drug development and are a common moiety in the pharmaceutical, agrochemical, and textile industries. Methods: The association between structural activity relationship data of many powerful compounds and their anticancer potential in vitro and in vivo has been studied. SAR of powerful heterocyclic compounds can also be generated using molecular docking simulations, as reported vastly in literature. Conclusions: Heterocycles have a wide range of applications, from natural compounds to synthesised derivatives with powerful anticancer properties. To avoid cytotoxicity or unfavourable effects on normal mammalian cells due to a lack of selectivity towards the target site, as well as to reduce the occurrence of drug resistance, safer anticancer lead compounds with higher potency and lower cytotoxicity are needed. This review emphasizes on design and development of heterocyclic lead compounds with promising anticancer potential.

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SYNTHESIS, MOLECULAR MODELING, AND QUANTITATIVE STRUCTURE–ACTIVITY RELATIONSHIP STUDIES OF UNDEC-10-ENEHYDRAZIDE DERIVATIVES AS ANTIMICROBIAL AGENTS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10s4.21344 ◽

2017 ◽

Vol 10 (16) ◽

pp. 94

Author(s):

Manju Kumari ◽

Rakesh Narang ◽

Surendra Kumar Nayak ◽

Sachin Kumar Singh ◽

Vivek Gupta ◽

...

Keyword(s):

Antimicrobial Activity ◽

Antimicrobial Agents ◽

Docking Study ◽

Quantitative Structure Activity Relationship ◽

Side Chain ◽

Quantitative Structure ◽

Molecular Docking Study ◽

Qsar Studies ◽

Structure Activity ◽

Methoxy Groups

Objective: In recent years, an increasing frequency and severity of antimicrobial resistance to different antimicrobial agents, demands new remedies for the treatment of infections. Therefore, in this study, a series of undec-10-enehydrazide derivatives were synthesized and screened for in vitro activity against selected pathogenic microbial strains.Methods: The synthesis of the intermediate and target compounds was performed by standard procedure. Synthesized compounds were screened for antimicrobial activity by tube dilution method. Molecular docking study of synthesized derivatives was also performed to find out their interaction with the target site of β-ketoacyl-acyl carrier protein synthase III, (FabH; pdb id:3IL7) by docking technique. Quantitative structure–activity relationship (QSAR) studies were also performed to correlate antimicrobial activity with structural properties of synthesized molecules.Results: Antimicrobial screening results showed that compound 8 having benzylidine moiety with methoxy groups at meta and para position and compound 16 having 3-chloro-2-(3-flourophenyl)-4-oxoazetidine moiety was found to be most potent. QSAR studies revealed the importance of Randic topology parameter (R) in describing the antimicrobial activity of synthesized derivatives. Molecular docking study indicated hydrophobic interaction of deeply inserted aliphatic side chain of the ligand with FabH. The N-atoms of hydrazide moiety interacts with Ala246 and Asn247 through H-bonding. The m- and p-methoxy groups form H-bond with water and side chain of Arg36, respectively.Conclusion: Compound 8 having benzylidine moiety with methoxy groups at meta and para position and compound 16 having 3-chloro-2-(3- flourophenyl)-4-oxoazetidine moiety was found to most potent antibacterial and antifungal compounds, respectively.

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