Substituted conformationally restricted guanidine derivatives: Probing the α2-adrenoceptors’ binding pocket

McMullan, Michela; García-Bea, Aintzane; Miranda-Azpiazu, Patrícia; Callado, Luís F.; Rozas, Isabel

doi:10.1016/j.ejmech.2016.07.011

Cited by 15 publications

(5 citation statements)

References 24 publications

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“…Continuing with our research in arylguanidine derivatives as α2-AR antagonists, − we have recently reported the pharmacological behavior of a series of guanidine derivatives of benzene ring-equivalents such as thiophene or thiazole at the α2-AR . We found interesting results in terms of affinity and activity (agonism vs antagonism) when comparing phenyl and pyridine cores within our in-house libraries.…”

Section: Introductionmentioning

confidence: 61%

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α₂-Adrenoceptors Ligands

Trujillo

Flood

Sánchez‐Sanz

et al. 2019

J. Chem. Inf. Model.

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A theoretical study has been carried out at the M062X/6-311++G(d,p) computational level to search for a rationale on ligands’ affinity toward α2-adrenoceptors by estimating the nature and strength of intramolecular hydrogen bonds potentially formed (by means of the QTAIM and NBO approaches) as well as the degree of deviation from planarity that could be observed in some of the compounds. Four different families have been studied: thiophen-2-yl, 3-carboxylatethiophen-2-yl esters, 3-cyanothiophen-2-yl, and 2-thiazolyl guanidinium derivatives. In the case of the thiophen-2-yl guanidines not substituted in the 3 position, nonplanarity was always observed, whereas in the thiazole series, intramolecular hydrogen bonds were identified between the guanidinium and the thiazole ring forcing the systems to planarity. Regarding the carboxylic esters, two different rotamers were found: quasi-planar and quasi-perpendicular systems with very similar energy. Both of these isomers can form different nets of intramolecular hydrogen bonds and other types of noncovalent interactions. Different physicochemical properties such as basicity, solubility, or lipophilicity were calculated for these systems, but no correlation to the degree of planarity was found. However, when comparing the α2-ARs affinity with the planarity of the molecules, a trend appears in the thiophen-2-yl guanidinium series indicating that lack of planarity seems to be optimal for α2-ARs engagement.

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Section: Introductionmentioning

confidence: 61%

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α₂-Adrenoceptors Ligands

Trujillo

Flood

Sánchez‐Sanz

et al. 2019

J. Chem. Inf. Model.

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“…McMullan therefore proposed to introduce a supplementary carbon atom to the guanidine ring to increase the system flexibility and thus insure better positioning of the compound within the receptor active site (1,3‐benzodiazepine derivatives). Compound 59 (Figure 30B) was found to have the highest affinity for the receptor (pKi = 6.64) and demonstrated antagonistic activity in vitro toward α‐2 receptors 255 …”

Section: Activity On G Protein‐coupled Receptors (Gpcrs)mentioning

confidence: 99%

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Malki

Martinez

Masurier

2021

Medicinal Research Reviews

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Privileged structures have been widely used as effective templates for drug discovery. While benzo‐1,4‐diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3‐diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved β‐lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring‐expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3‐diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3‐diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.

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“…As an important seven-membered N-heterocycle, azepine occurred widely in natural products and biologically active molecules (Scheme 2). [4] For instance, galantamine is a drug for treating alzheimer's disease, myasthenia gravis, and other sensory or movement disorder diseases. Fawcettimine, with its azepine intergrated ring system, is one natural product that shows important biological activity.…”

Section: Azepine Skeletons In Natural Products and Biologically Activmentioning

confidence: 99%

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

Ouyang

Rao

et al. 2020

Adv Synth Catal

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Medium N-heterocycles, azepines and azocines, serve as important skeletons that occurred widely in natural products, however, due to the lack of efficient synthetic methodologies, their application potential in biologically active molecules, pharmaceuticals and agrochemicals remained to be explored. In this context, rhodium catalysis in this field featured good reactivity and functional group tolerance, with readily available starting materials, and enabled rapid access to the azepines and azocines. Delightfully, great achievements in the concise construction of these 7 and 8-membered N-heterocycles under rhodium catalysis have been made, which mainly included cycloisomerization of unsaturated CÀ X bonds (which might also combine the ring-opening strategy on strained rings), metal carbenoid or nitrene insertion involved transformations and direct CÀ H activation reactions. Considering the great performance of rhodium catalyst in the synthesis of azepines and azocines, herein, we summarized the recent results in this field, and wish to give further insight and inspired more encouraging methodologies and new drug discovery based on these 7 and 8membered N-heterocycles.

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Substituted conformationally restricted guanidine derivatives: Probing the α2-adrenoceptors’ binding pocket

Cited by 15 publications

References 24 publications

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α₂-Adrenoceptors Ligands

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α₂-Adrenoceptors Ligands

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

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Substituted conformationally restricted guanidine derivatives: Probing the α2-adrenoceptors’ binding pocket

Cited by 15 publications

References 24 publications

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α2-Adrenoceptors Ligands

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α2-Adrenoceptors Ligands

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

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Product

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Planarity or Nonplanarity: Modulating Guanidine Derivatives as α₂-Adrenoceptors Ligands

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α₂-Adrenoceptors Ligands