Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and SAR studies on azetidine-containing dipeptides as HCMV inhibitors.

ABSTRACT: SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti-HCMV activity. The conformational restriction induced by the 2-azetidine residue into the dipeptide derivatives, identified by (1)H NMR as a γ-type reverse turn, seems to have influence on the activity of these molecules.

SUBMITTER: Perez-Faginas P

PROVIDER: S-EPMC7127091 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and SAR studies on azetidine-containing dipeptides as HCMV inhibitors.

Pérez-Faginas Paula P Aranda M Teresa MT García-López M Teresa MT Snoeck Robert R Andrei Graciela G Balzarini Jan J González-Muñiz Rosario R

Bioorganic & medicinal chemistry 20101230 3

SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti-HCMV activity. The conformational re ...[more]

PMID: 21256035

Similar Datasets

Synthesis of Cycloheptatriene-Containing Azetidine Lactones.

Project description:We prepared a collection of complex cycloheptatriene-containing azetidine lactones by applying two key photochemical reactions: "aza-Yang" cyclization and Buchner carbene insertion into aromatic rings. While photolysis of phenacyl amines leads to a rapid charge transfer and elimination, we found that a simple protonation of the amine enables the formation of azetidinols as single diastereomers. We provide evidence, through ultrafast spectroscopy, for the electron transfer from free amines in the excited state. Further, we characterize the aza-Yang reaction by establishing the dependence of the initial reaction rates on the rates of photon absorption. An unanticipated change in reactivity in morpholine analogues is explained through interactions with the tosylate anion. The Buchner reaction proceeds with a slight preference for one diastereomer over the other, and successful reaction requires electron-donating carbene-stabilizing substituents. Overall, 16 compounds were prepared over seven steps. Guided by an increase in structural complexity, efforts such as this one extend the reach of chemists into unexplored chemical space and provide useful quantities of new compounds for studies focused on their properties.

| S-EPMC10091648 | biostudies-literature

Facilitated synthesis of proteins containing modified dipeptides.

Project description:The elaboration of peptides and proteins containing non-proteinogenic amino acids has been realized using several complementary strategies, including chemical synthesis, ribosome- or non-ribosome-mediated elaboration, intein-mediated polypeptide rearrangements, or some combination of these strategies. All of these have strengths and limitations, and significant efforts have been focused on minimizing the effects of limitations, to improve the overall utility of individual strategies. Our laboratory has studied ribosomally mediated peptide and protein synthesis involving a wide variety of non-proteinogenic amino acids, and in recent years we have described a novel strategy for the selection of modified bacterial ribosomes. These modified ribosomes have enabled the incorporation into peptides and proteins of numerous modified amino acids not accessible using wild-type ribosomes. This has included d-amino acids, β-amino acids, dipeptides and dipeptidomimetic species, as well as phosphorylated amino acids. Presently, we have considered novel strategies for incorporating non-proteinogenic amino acids in improved yields. This has included the incorporation of non-proteinogenic amino acids into contiguous positions, a transformation known to be challenging. We demonstrate the preparation of this type of protein modification by utilizing a suppressor tRNACUA activated with a dipeptide consisting of two identical non-proteinogenic amino acids, in the presence of modified ribosomes selected to recognize such dipeptides. Also, we demonstrate that the use of bis-aminoacylated suppressor tRNAs, shown previously to increase protein yields significantly in vitro, can be extended to the use of non-proteinogenic amino acids.

| S-EPMC8217302 | biostudies-literature

Synthesis and SAR studies of dual AKT/NF-κB inhibitors against melanoma.

Project description:The protein Kinase B alpha (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways are central regulators of cellular signaling events at the basis of tumor development and progression. Both pathways are often up-regulated in different tumor types including melanoma. We recently reported the identification of compound 1 (BI-69A11) as inhibitor of the AKT and the NF-κB pathways. Here, we describe SAR studies that led to novel fluorinated derivatives with increased cellular potency, reflected in efficient inhibition of AKT and IKKs. Selected compounds demonstrated effective toxicity on melanoma, breast, and prostate cell lines. Finally, a representative derivative showed promising efficacy in an in vivo melanoma xenograft model.

| S-EPMC3966491 | biostudies-literature

Anthrax lethal factor protease inhibitors: synthesis, SAR, and structure-based 3D QSAR studies.

Project description:We have recently identified a series of compounds that efficiently inhibit anthrax lethal factor (LF) metallo-protease. Here we present further structure-activity relationship and CoMFA (comparative molecular field analysis) studies on newly derived inhibitors. The obtained 3D QSAR model was subsequently compared with the X-ray structure of the complex between LF and a representative compound. Our studies form the basis for the rational design of additional compounds with improved activity and selectivity.

| S-EPMC3164827 | biostudies-literature

Theoretical Studies of Cyanophycin Dipeptides as Inhibitors of Tyrosinases.

Project description:The three-dimensional structure of tyrosinase has been crystallized from many species but not from Homo sapiens. Tyrosinase is a key enzyme in melanin biosynthesis, being an important target for melanoma and skin-whitening cosmetics. Several studies employed the structure of tyrosinase from Agaricus bisporus as a model enzyme. Recently, 98% of human genome proteins were elucidated by AlphaFold. Herein, the AlphaFold structure of human tyrosinase and the previous model were compared. Moreover, tyrosinase-related proteins 1 and 2 were included, along with inhibition studies employing kojic and cinnamic acids. Peptides are widely studied for their inhibitory activity of skin-related enzymes. Cyanophycin is an amino acid polymer produced by cyanobacteria and is built of aspartic acid and arginine; arginine can be also replaced by other amino acids. A new set of cyanophycin-derived dipeptides was evaluated as potential inhibitors. Aspartate-glutamate showed the strongest interaction and was chosen as a leading compound for future studies.

| S-EPMC8950311 | biostudies-literature

Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: novel antibacterial agents against Mycobacterium tuberculosis.

Project description:Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.

| S-EPMC2956582 | biostudies-literature

In Silico SAR Studies of HIV-1 Inhibitors.

Project description:Quantitative Structure Activity Relationships (QSAR or SAR) have helped scientists to establish mathematical relationships between molecular structures and their biological activities. In the present article, SAR studies have been carried out on 89 tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine (TIBO) derivatives using different classifiers, such as support vector machines, artificial neural networks, random forests, and decision trees. The goal is to propose classification models that will be able to classify TIBO compounds into two groups: high and low inhibitors of HIV-1 reverse transcriptase. Each molecular structure was encoded by 10 descriptors. To check the validity of the established models, all of them were subjected to various validation tests: internal validation, Y-randomization, and external validation. The established classification models have been successful. The correct classification rates reached 100% and 90% in the learning and test sets, respectively. Finally, molecular docking analysis was carried out to understand the interactions between reverse transcriptase enzyme and the TIBO compounds studied. Hydrophobic and hydrogen bond interactions led to the identification of active binding sites. The established models could help scientists to predict the inhibition activity of untested compounds or of novel molecules prior to their synthesis. Therefore, they could reduce the trial and error process in the design of human immunodeficiency virus (HIV) inhibitors.

| S-EPMC6160994 | biostudies-literature

SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents.

Project description:Recently, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for drug discovery of next-generation antifungal agents, and we found two aromatic acylhydrazones as effective inhibitors of GlcCer synthesis based on HTP screening. In the present work, we have designed libraries of new aromatic acylhydrazones, evaluated their antifungal activities (MIC80 and time-kill profile) against C. neoformans, and performed an extensive SAR study, which led to the identification of five promising lead compounds, exhibiting excellent fungicidal activities with very large selectivity index. Moreover, two compounds demonstrated broad spectrum antifungal activity against six other clinically relevant fungal strains. These five lead compounds were examined for their synergism/cooperativity with five clinical drugs against seven fungal strains, and very encouraging results were obtained; e.g., the combination of all five lead compounds with voriconazole exhibited either synergistic or additive effect to all seven fungal strains.

| S-EPMC6755904 | biostudies-literature

Elucidating bis-pyrimidines as new and efficient mushroom tyrosinase inhibitors: synthesis, SAR, kinetics and computational studies.

Project description:In this study, a series of novel bis-pyrimidine derivatives (1P-8P) were designed, synthesized, characterized, and investigated for their in vitro inhibitory activity against mushroom tyrosinase, an enzyme critical in melanin biosynthesis and implicated in various hyperpigmentation disorders. To the best of our knowledge, the bispyrimidine scaffold has been evaluated for the first time for its tyrosinase inhibitory activity. Their inhibitory activities were assessed, revealing inhibition with IC50 values in the micromolar range. Additionally, this series of compounds were found to inhibit tyrosinase activity in a mixed-type manner, with IC50 values ranging from 12.36 ± 1.24 to 86.67 ± 3.08 μM. To further elucidate the binding interactions, molecular docking simulations were performed, identifying key residues in the active site responsible for binding affinity. Furthermore, molecular dynamics (MD) simulations were conducted to assess the dynamic behavior, stability, and binding affinity of the most potent inhibitor, compound 6P. Quantitative Structure-Activity Relationship (QSAR) models were developed to correlate the structural features of the bis-pyrimidines with their inhibitory activity, providing insights into the structure-activity relationships (SAR) that govern their potency. The experimental and theoretical findings demonstrated excellent agreement. These findings pave the way for the development of novel bis-pyrimidine-based therapeutic agents for treating hyperpigmentation and related conditions.

| S-EPMC11258615 | biostudies-literature

Design and synthesis of highly potent and isoform selective JNK3 inhibitors: SAR studies on aminopyrazole derivatives.

Project description:The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure-activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.

| S-EPMC4266361 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data