Pharmacophore Searching of Benzofuran Derivatives for Selective CYP19 Aromatase Inhibition
About: This article is published in Letters in Drug Design & Discovery.The article was published on 2009-01-01. It has received 8 citations till now. The article focuses on the topics: Pharmacophore & Benzofuran.
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TL;DR: This work systematically gives a comprehensive review in current developments of imidazole‐based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti‐inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology.
Abstract: Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.
558 citations
TL;DR: An account of recent developments in the AI field from the perspective of the enzyme's structure-function relationships is presented.
Abstract: Human aromatase catalyzes the synthesis of estrogen from androgen with high substrate specificity. For the past 40 years, aromatase has been a target of intense inhibitor discovery research for the prevention and treatment of estrogen-dependent breast cancer. The so-called third generation aromatase inhibitors (AIs) letrozole, anastrozole, and the steroidal exemestane were approved in the U.S. in the late 1990s for estrogen-dependent postmenopausal breast cancer. Efforts to develop better AIs with higher selectivity and lower side effects were handicapped by the lack of an experimental structure of this unique P450. The year 2009 marked the publication of the crystal structure of aromatase purified from human placenta, revealing an androgen-specific active site. The structure has reinvigorated research activities on this fascinating enzyme and served as the catalyst for next generation AI discovery research. Here, we present an account of recent developments in the AI field from the perspective of the enz...
65 citations
TL;DR: A series of androstenedione derivatives with CYP19 inhibitory activity was subjected to a molecular docking study followed by quantitative structure–activity relationship (QSAR) analyses in search of ideal physicochemical characteristics of potential aromatase inhibitors.
Abstract: Objectives Aromatase (CYP19) inhibitors have emerged as promising candidates for the treatment of estrogen-dependent breast cancer. In this study, a series of androstenedione derivatives with CYP19 inhibitory activity was subjected to a molecular docking study followed by quantitative structure–activity relationship (QSAR) analyses in search of ideal physicochemical characteristics of potential aromatase inhibitors.
Methods The QSAR studies were carried out using both two-dimensional (topological, and structural) and three-dimesional (spatial) descriptors. We also used thermodynamic parameters along with 2D and 3D descriptors. Genetic function approximation (GFA) and genetic partial least squares (G/PLS) were used as chemometric tools for QSAR modelling.
Key findings The docking study indicated that the important interacting amino acids in the active site were Met374, Arg115, Ile133, Ala306, Thr310, Asp309, Val370, Leu477 and Ser478. The 17-keto oxygen of the ligands is responsible for the formation of a hydrogen bond with Met374 and the remaining parts of the molecules are stabilized by the hydrophobic interactions with the non-polar amino acids. The C2 and C19 positions in the ligands are important for maintaining the appropriate orientation of the molecules in the active site. The results of docking experiments and QSAR studies supported each other.
Conclusions The developed QSAR models indicated the importance of some Jurs parameters, structural parameters, topological branching index and E-state indices of different fragments. All the developed QSAR models were statistically significant according to the internal and external validation parameters.
36 citations
Cites background from "Pharmacophore Searching of Benzofur..."
...A few quantitative structure–activity relationship (QSAR) studies have also been reported on selected classes of aromatase inhibitors.([37,38]) The binding characteristics and interactions of steroidal aromatase inhibitors in the active site, as well the properties important for binding (electronic, hydrophobic and steric features), are required to be explored in designing more selective aromatase inhibitors....
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TL;DR: In this article, a recyclingable catalytic synthesis of benzofuran-2-acetic esters by sequential Pd(0)-catalyzed deallylation and PdI2-car catalyzed carbonylative heterocyclization in ionic liquids is presented.
Abstract: A convenient, recyclable catalytic synthesis of benzofuran-2-acetic esters 2 by sequential Pd(0)-catalyzed deallylation—Pd(II)-catalyzed carbonylative heterocyclization of 1-(2-allyloxyphenyl)-2-yn-1-ols 1 in ionic liquids is presented. Reactions were typically carried out in BmimBF4 as the solvent at 100 °C and under 30 atm of CO, in the presence of catalytic amounts (1 mol %) of PdI2 in conjunction with KI (1 equiv), PPh3 (4 mol %), MeOH (28 equiv), and H2O (2 equiv). The solvent-catalyst system could be recycled several times without appreciable loss of catalytic activity.
22 citations
01 Jan 2015
TL;DR: Different LBDD and SBDD approaches are presented here to understand their utility in designing novel NSAIs, and pharmacophore mapping followed by virtual screening, docking, and dynamic simulation may be effective approaches for designing new potent anti-aromatase molecules.
Abstract: Aromatase is a multienzyme complex overexpressed in breast cancer and responsible for estrogen production. It is the potential target for designing anti-breast cancer drugs. Ligand and Structure-Based Drug Designing approaches (LBDD and SBDD) are involved in development of active and more specific Nonsteroidal Aromatase Inhibitors (NSAIs). Different LBDD and SBDD approaches are presented here to understand their utility in designing novel NSAIs. It is observed that molecules should possess a five or six membered heterocyclic nitrogen containing ring to coordinate with heme portion of aromatase for inhibition. Moreover, one or two hydrogen bond acceptor features, hydrophobicity, and steric factors may play crucial roles for anti-aromatase activity. Electrostatic, van der Waals, and π-π interactions are other important factors that determine binding affinity of inhibitors. HQSAR, LDA-QSAR, GQSAR, CoMFA, and CoMSIA approaches, pharmacophore mapping followed by virtual screening, docking, and dynamic simulation may be effective approaches for designing new potent anti-aromatase molecules.
9 citations