scholarly journals Synthesis of New Imidazopyridine Nucleoside Derivatives Designed as Maribavir Analogues

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4531
Author(s):  
Georgios Papadakis ◽  
Maria Gerasi ◽  
Robert Snoeck ◽  
Panagiotis Marakos ◽  
Graciela Andrei ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Human Cytomegalovirus ◽  
Structural Modification ◽  
Central Core ◽  
Strong Inhibition ◽  
Cytotoxic Potential ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Hcmv Replication ◽  
New Compounds

The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure–activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.

scholarly journals Discovery of New Inhibitors of Transforming Growth Factor-Beta Type 1 Receptor by Utilizing Docking and Structure-Activity Relationship Analysis

2019 ◽  
Vol 20 (17) ◽  
pp. 4090 ◽  
Author(s):  
Jiang ◽  
Deng
Keyword(s):  
Molecular Docking ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Binding Modes ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Growth Factor Beta ◽  
New Compounds

The transforming growth factor-beta (TGF-β) plays an important role in pathological fibrosis and cancer transformation. Therefore, the inhibition of the TGF-β signaling pathway has therapeutic potential in the treatment of cancer. In this study, the binding modes between 47 molecules with a pyrrolotriazine-like backbone structure and transforming growth factor-beta type 1 receptor (TβR1) were simulated by molecular docking using Discovery Studio software, and their structure–activity relationships were analyzed. On the basis of the analysis of the binding modes of ligands in the active site and the structure–activity relationships, 29,254 new compounds were designed for virtual screening. According to the aforementioned analyses and Lipinski’s rule of five, five new compounds (CQMU1901–1905) with potential activity were screened through molecular docking. Among them, CQMU1905 is an attractive molecule composed of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), and 5-azacytosine. Interestingly, 5-FU, 6-MP, and 5-azacytidine are often used as anti-metabolic agents in cancer treatment. Compared with existing compounds, CQMU1901–1905 can interact with target proteins more effectively and have good potential for modification, making them worthy of further study.

scholarly journals The Structure-Activity Relationships of 2,4(1H,3H)-pyrimidinedione Derivatives as potent HIV type 1 and type 2 inhibitors

2007 ◽  
Vol 18 (5) ◽  
pp. 259-275 ◽  
Author(s):  
Robert W Buckheit ◽  
Tracy L Hartman ◽  
Karen M Watson ◽  
Ho Seok Kwon ◽  
Sun Hwan Lee ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Binding Pocket ◽  
Target Cells ◽  
Significant Activity ◽  
In Vitro Test ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Test Concentration ◽  
Hiv 1

Since the discovery of the 2,4 (1 H,3 H)-pyrimidinediones as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase (RT) this class of compounds has yielded a number of N-1 acyclic substituted pyrimidinediones with substantial antiviral activity, which is highly dependent upon their molecular fit into the binding pocket common to this inhibitory class. We have specifically examined the structure activity relationships of compounds with chemical modification made by substituting homocyclic rather than acyclic moieties at N-1 of the pyrimidinedione. Seventy-four compounds were synthesized and evaluated for antiviral activity against HIV-1 and HIV-2. The homocyclic modifications resulted in compounds with significant activity against both HIV-1 and HIV-2, suggesting these compounds represent a new class of non-nucleoside RT inhibitors. The structure-activity relationship (SAR) evaluations indicated that cyclopropyl, phenyl and 1- or 3-cyclopenten-1-yl substitutions at the N-1 of the pyrimidinedione, the addition of a methyl linker between the cyclic moiety and the N-1 and the addition of a benzoyl group at the C-6 of the pyrimidinedione had the greatest contribution to antiviral activity. Five pyrimidinedione analogues with therapeutic indexes (TIs)>450,000 and a specific analogue (1-cyclopropylmethyl-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4(1 H,3 H)-pyrimidinedione), which exhibited a TI of >2,000,000, were identified. None of the analogues were cytotoxic to target cells at the highest in vitro test concentration, which is the upper limit of compound solubility of the analogues in aqueous solution. Thus, we have identified a series of pyrimidinediones with substantially improved antiviral efficacy and range of action and with significantly reduced cellular cytotoxicity.

Novel Non-Nucleoside Human Cytomegalovirus Inhibitors Based Upon Tsao Nucleoside Derivatives: Structure-Activity Relationships

2007 ◽  
Vol 26 (6-7) ◽  
pp. 625-628 ◽  
Author(s):  
Sonia de Castro ◽  
Graziela Andrei ◽  
Robert Snoeck ◽  
Jan Balzarini ◽  
María-José Camarasa ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Structure Activity Relationships ◽  
Structure Activity

scholarly journals Calix[4]arene Sulfonate Hosts Selectively Modified on the Upper Rim: A Study of Nicotine Binding Strength and Geometry

2021 ◽  
Author(s):  
Zoey Warmerdam ◽  
Bianca Kamba ◽  
Alok Shaurya ◽  
XuXin Sun ◽  
Mary Maguire ◽  
...  
Keyword(s):  
Association Constants ◽  
Binding Studies ◽  
Binding Strength ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Binding Data ◽  
Displacement Based ◽  
New Compounds ◽  
Upper Rim ◽  
Nmr Titrations

Preprint manuscript, including synthesis of new compounds and fluorescence/NMR-based binding data. <div><br></div><div>We present the synthesis and structure-activity relationships of sulfonatocalix[4]arene hosts bearing novel substitutions. The calix[4]arenes are modified on the upper rim at either one or two of the phenolic units, where the dual modifications are introduced selectively on neighboring or opposing phenols. The calix[4]arenes are mono- or di-functionalized with nitro or formyl groups, with the remaining upper-rim sites in all cases occupied by sulfonates. Equilibrium association constants were determined between each host and the guests nicotine, nornicotine, and cotinine. Indicator displacement-based binding studies show that nicotine binds most strongly to the different members of the library followed by nornicotine, whereas cotinine displays weak to no binding. NMR titrations were carried out with nicotine and show different host-guest interaction geometries for the formyl-calix[4]arenes versus the nitro-calix[4]arenes. <div><p></p></div></div>

The Current Status and Future Applicability of Quantitative Structure–activity Relationships (QSARs) in Predicting Toxicity

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 81-84 ◽  
Author(s):  
Mark T.D. Cronin
Keyword(s):  
Chemical Structure ◽  
Current Status ◽  
Regulatory Agencies ◽  
Toxicity Data ◽  
Quantitative Structure ◽  
Structure Activity Relationships ◽  
The Poor ◽  
Structure Activity ◽  
Quantitative Structure Activity Relationships ◽  
New Compounds

The current status of quantitative structure–activity relationships (QSARs) in predicting toxicity is assessed. Widespread use of these methods to predict toxicity from chemical structure is possible, both by industry to develop new compounds, and also by regulatory agencies. The current use of QSARs is restricted by the lack of suitable toxicity data available for modelling, the unsuitability of simplistic modelling approaches for the prediction of certain endpoints, and the poor definition and utilisation of the applicability domain of models. Suggestions to resolve these issues are made.

scholarly journals Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396

2016 ◽  
Vol 90 (18) ◽  
pp. 8181-8197 ◽  
Author(s):  
Christopher Murgatroyd ◽  
Lisa Pirrie ◽  
Fanny Tran ◽  
Terry K. Smith ◽  
Nicholas J. Westwood ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Betulinic Acid ◽  
Proteolytic Processing ◽  
Structure Activity Relationships ◽  
Modes Of Action ◽  
Structure Activity ◽  
Essential Properties ◽  
Maturation Inhibitor ◽  
The Relationship ◽  
Hiv 1

ABSTRACTHIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) thetert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated.IMPORTANCECombinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action.

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