Discovery of cyclopentane- and cyclohexane-trans-1,3-diamines as potent melanin-concentrating hormone receptor 1 antagonists

Giordanetto, Fabrizio; Karlsson, Olle; Lindberg, Jimmy; Larsson, Lars-Olof; Linusson, Anna; Evertsson, Emma; Morgan, David; Inghardt, Tord

doi:10.1016/j.bmcl.2007.05.034

Cited by 24 publications

(14 citation statements)

References 22 publications

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“…To the best of our knowledge so far [ 29 , 32 , 38 , 39 , 42 , 43 , 46 , 47 , 48 , 49 , 50 , 51 ], two MCHR1 binding pockets (listed as P1 and P2, respectively) have been proposed. P1 represents the conventional binding cavity that almost all docking researches have referred to where a typical interaction of salt bridge is found experimentally formed by Asp123, and simultaneously H-bond or hydrophobic regions may also be embodied.…”

Section: Resultsmentioning

confidence: 99%

Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

et al. 2014

IJMS

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Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure–activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q2) = 0.509, non-cross-validated correlation coefficient (R2ncv) = 0.841 and the predicted correlation coefficient (R2pred) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.

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Section: Resultsmentioning

confidence: 99%

Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

et al. 2014

IJMS

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“…Moderate (10–60 %) to high conversions were also observed with aliphatic amines, including the formation of N ‐(thiophen‐3‐ylmethyl)cyclohexanamine ( 4 a ), the core of a potent melanin‐concentrating hormone receptor antagonist and the chemical synthesis of which was reported as tedious and low yielding . Moderate conversions into amphetamine analogues 6 b and 7 b were observed after reductive amination of p ‐fluorophenylacetone ( b ) with methylamine ( 6 ) and propargylamine ( 7 ).…”

Section: Methodsmentioning

confidence: 99%

Efficient Biocatalytic Reductive Aminations by Extending the Imine Reductase Toolbox

et al. 2017

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Chiral secondary and tertiary amines are ubiquitous in pharmaceutical, fine, and specialty chemicals, but their synthesis typically suffers from significant sustainability and selectivity challenges. Biocatalytic alternatives, such as enzyme‐catalyzed reductive amination, offer several advantages over traditional chemistry, but industrial applicability has not yet been demonstrated. Herein, we report the use of cell lysates expressing imine reductases operating at 1:1 stoichiometry for a variety of amines and carbonyls. A collection of biocatalysts with diversity in coverage of small molecules and direct industrial applicability is presented.

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“…1,2,4 Triazines documented as anti HIV, anti H5N1 virus agents [12][13][14] are also antiproleferative [15,16] agents acting on VEGFR tyrosine kinases [17] as well as anti tuberculosis [18], anti anxiety, anti inflammatory agents [19,20], potent antidepression and antianxiety agents [21], and anti breast cancer candidates [22]. Finally, thiophenes are well known as inhibitors of BACE1 preventing β amyloid plaques formation in Alzheimer's disease [23,24] and Plasmo dium falciparum differentiation [25], anti HIV [26], antiproleferative [27,28], anti inflammatory [29][30][31], antibacterial [32], and antiprotozoal [33] agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, reactions, and biological activity of some triazine derivatives containing sulfa drug moieties

et al. 2015

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Thienyl-triazine-sulphonamide conjugates were prepared from their precursor amines using triethyl orthoformate or ethyl chloroformate as cross coupling reagents. The progress of these reactions was investigated by spectral (IR, NMR, MS) and microanalytical techniques. The synthesized compounds were in vitro screened for antibacterial, antifungal, antioxidant, and anticancer activity. 4-[({[3-Mercapto-5-oxo-6-[2-(2-thienyl)yinyl]-1,2,4-triazin- 4(5H)-yl]imino}methyl)amino]-benzenesulfonamide turned out to be a powerful antibacterial agent, while all the compounds prepared were inactive against fungal species tested. 4-{[({8-Cyano-4-oxo-3-[2-(2-thienyl)vinyl- 4H,8H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-7-yl}amino)(ethoxy)methyl]amino}benzenesulfonamide displayed in vitro promising cytotoxicity against Ehrlich ascites carcinoma cell line with concurrent attenuation of malonodinitrile and it was unique among other compounds being unable to increase glutathione S-transferase and reduced glutathione S-transferase activities. This compound exhibited also good antioxidant properties that together with its cytotoxicity nominated it for further investigation in cancer research.

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Discovery of cyclopentane- and cyclohexane-trans-1,3-diamines as potent melanin-concentrating hormone receptor 1 antagonists

Cited by 24 publications

References 22 publications

Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

Efficient Biocatalytic Reductive Aminations by Extending the Imine Reductase Toolbox

Synthesis, reactions, and biological activity of some triazine derivatives containing sulfa drug moieties

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