Triazolinone Biphenylsulfonamide Derivatives as Orally Active Angiotensin II Antagonists with Potent AT1 Receptor Affinity and Enhanced AT2 Affinity

Ashton, Wallace T.; Chang, Linda; Flanagan, Kelly L.; Hutchins, Steven M.; Naylor, Elizabeth M.; Chakravarty, Prasun K.; Patchett, Arthur A.; Greenlee, William J.; Chen, Tsing-Bau

doi:10.1021/jm00043a020

Cited by 38 publications

(14 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 (a). The configuration cost was 14.23, which is in agreement to standard requirement of configuration (Ashton et al, 1994) cost that should not exceed a maximum value of 17 (corresponds to a number of 2 17 pharmacophore models) because high values may lead to a chance correlation of the generated hypothesis. Thus, hypothesis 1 was considered as the best pharmacophore model for NMDA inhibitory activity and was used to predict the activity of all the 17 training set compounds.…”

Section: Pharmacophore Generationsupporting

confidence: 81%

Identification of novel and structurally diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking

Sharma

Mittal

Singh

et al. 2018

Preprint

View full text Add to dashboard Cite

In view of "excitotoxic" effects of glutamate, wherein excessive excitatory input causes increase in intracellular Ca 2+ and ultimately cell death, NMDA receptor has emerged as an important target for treatment and prevention of several neurological disorders, like Alzheimer disease.Prompted by the successful application of in-silico pharmacophore-based virtual screening in lead identification, we have made an effort to implement in-silico protocols to identify novel NMDA receptor antagonist. A series of novel benzo[b]quinolizinium cations as NMDA receptor antagonists have been used as a starting point to develop prognostic pharmacophore models. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, one hydrogen bond acceptor, one hydrophobic and two ring aromatic, showed a correlation (r) of 0.89, root mean square of 0.259, and the cost difference of 43.01 bits between null and fixed cost. The model was thoroughly validated and subjected to a chemical database search, which lead to the identification of 400 hits from NCI and Maybridge databases which were checked for Lipinski's violation and predictive potency. This reduced the list to 10 compounds, out of which, two most potent compounds were subjected to molecular docking using Libdock software and interestingly, all the docked conformations showed hydrogen bond interactions with important amino acids Tyr214, His88, Thr174, Val169 and Arg121. In summary, through our validated pharmacophore-based virtual screening protocol, we have identified two potent, structurally diverse, druggable and novel NMDA receptor antagonist which might be of great help to address the unmet medical need of Alzheimer disease.

show abstract

Section: Pharmacophore Generationsupporting

confidence: 81%

Identification of novel and structurally diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking

Sharma

Mittal

Singh

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Hypothesis1 had total cost close to fixed cost (124.52), lower error cost (103.409), lowest root-mean-square (RMS) divergence (0.408), best correlation ( r = 0.977), and good internal test set prediction ( r test-set = 0.93). The configuration cost of the hypothesis exceeded the limit of 17 bits but can be accepted as the model achieves other validation criterion [11,12]. …”

Section: Resultsmentioning

confidence: 99%

In silico identification of novel lead compounds with AT1 receptor antagonist activity: successful application of chemical database screening protocol

Pal

Paliwal

2012

Organic and Medicinal Chemistry Letters

View full text Add to dashboard Cite

BackgroundAT1 receptor antagonists are clinically effective drugs for the treatment of hypertension, cardiovascular, and related disorders. In an attempt to identify new AT1 receptor antagonists, a pharmacophore-based virtual screening protocol was applied. The pharmacophore models were generated from 30 training set compounds. The best model was chosen on the basis of squared correlation coefficient of training set and internal test set. The validity of the developed model was also ensured using catScramble validation method and external test set prediction.ResultsThe final model highlighted the importance of hydrogen bond acceptor, hydrophobic aliphatic, hydrophobic, and ring aromatic features. The model satisfied all the statistical criteria such as cost function analysis and correlation coefficient. The result of estimated activity for internal and external test set compounds reveals that the generated model has high prediction capability. The validated pharmacophore model was further used for mining of 56000 compound database (MiniMaybridge). Total 141 hits were obtained and all the hits were checked for druggability, this led to the identification of two active druggable AT1 receptor antagonists with diverse structure.ConclusionA highly validated pharmacophore model generated in this study identified two novel druggable AT1 receptor antagonists. The developed model can also be further used for mining of other virtual database.

show abstract

“…N -acylsulfonamide (sulfacetamide) is well known basic common structural motif [1], which is present as a functional group in a wide range of therapeutics [2]. The formation of N -acylsulfonamides (sulfacetamides) is synthetically important for easy access to various structures [3]. Molecules containing acylsulfonamide (sulfacetamide) functional groups have been explored as HCV protease inhibitors and CXCR 2 antagonists [4].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Density Functional Theory (DFT), Urease Inhibition and Antimicrobial Activities of 5-Aryl Thiophenes Bearing Sulphonylacetamide Moieties

et al. 2015

View full text Add to dashboard Cite

A variety of novel 5-aryl thiophenes 4a-g containing sulphonylacetamide (sulfacetamide) groups were synthesized in appreciable yields via Pd[0] Suzuki cross coupling reactions. The structures of these newly synthesized compounds were determined using spectral data and elemental analysis. Density functional theory (DFT) studies were performed using the B3LYP/6-31G (d, p) basis set to gain insight into their structural properties. Frontier molecular orbital (FMOs) analysis of all compounds 4a-g was computed at the same level of theory to get an idea about their kinetic stability. The molecular electrostatic potential (MEP) mapping over the entire stabilized geometries of the molecules indicated the reactive sites. First hyperpolarizability analysis (nonlinear optical response) were simulated at the B3LYP/6-31G (d, p) level of theory as well. The compounds were further evaluated for their promising antibacterial and anti-urease activities. In this case, the antibacterial activities were estimated by the agar well diffusion method, whereas the anti-urease activities of these compounds were determined using the indophenol method by quantifying the evolved ammonia produced. The results revealed that all the sulfacetamide derivatives displayed antibacterial activity against Bacillus subtiles, Escherichia coli, Staphylococcus aureus, Shigella dysenteriae, Salmonella typhae, Pseudomonas aeruginosa at various concentrations. Furthermore, the compound 4g N-((5-(4-chlorophenyl)thiophen-2-yl)sulfonyl) acetamide showed excellent urease inhibition with percentage inhibition activity~46.23˘0.11 at 15 µg/mL with IC 50 17.1 µg/mL. Moreover, some other compounds 4a-f also exhibited very good inhibition against urease enzyme.

show abstract

Triazolinone Biphenylsulfonamide Derivatives as Orally Active Angiotensin II Antagonists with Potent AT1 Receptor Affinity and Enhanced AT2 Affinity

Cited by 38 publications

References 12 publications

Identification of novel and structurally diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking

Identification of novel and structurally diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking

In silico identification of novel lead compounds with AT1 receptor antagonist activity: successful application of chemical database screening protocol

Synthesis, Density Functional Theory (DFT), Urease Inhibition and Antimicrobial Activities of 5-Aryl Thiophenes Bearing Sulphonylacetamide Moieties

Contact Info

Product

Resources

About