scholarly journals Bromo-Cyclobutenaminones as New Covalent UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors

2020 ◽  
Vol 13 (11) ◽  
pp. 362
Author(s):  
David J. Hamilton ◽  
Péter Ábrányi-Balogh ◽  
Aaron Keeley ◽  
László Petri ◽  
Martina Hrast ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Nucleophilic Substitution ◽  
Crucial Role ◽  
Bromine Atom ◽  
Activity Relationship ◽  
Structure Activity ◽  
Starting Point ◽  
Covalent Inhibitors ◽  
Electrophilic Reactivity ◽  
Antibacterial Target

Drug discovery programs against the antibacterial target UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and five-membered heterocyclic rings. In the current study, the reactivity of four-membered rings was carefully modulated to obtain a novel family of covalent MurA inhibitors. Screening a small library of cyclobutenone derivatives led to the identification of bromo-cyclobutenaminones as new electrophilic warheads. The electrophilic reactivity and cysteine specificity have been determined in a glutathione (GSH) and an oligopeptide assay, respectively. Investigating the structure-activity relationship for MurA suggests a crucial role for the bromine atom in the ligand. In addition, MS/MS experiments have proven the covalent labelling of MurA at Cys115 and the observed loss of the bromine atom suggests a net nucleophilic substitution as the covalent reaction. This new set of compounds might be considered as a viable chemical starting point for the discovery of new MurA inhibitors.

Triazol: a privileged scaffold for proteolysis targeting chimeras

2019 ◽  
Vol 11 (22) ◽  
pp. 2919-2973 ◽  
Author(s):  
Li-Wen Xia ◽  
Meng-Yu Ba ◽  
Wei Liu ◽  
Weyland Cheng ◽  
Chao-Ping Hu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Anticancer Activity ◽  
Mode Of Action ◽  
Critical Analysis ◽  
Enzyme Inhibitors ◽  
Structure Activity Relationship ◽  
Target Protein ◽  
Activity Relationship ◽  
Structure Activity ◽  
Privileged Scaffold

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

Kernel Methods in Chemoinformatics

2011 ◽  
pp. 664-668
Author(s):  
Huma Lodhi
Keyword(s):  
Developing Countries ◽  
Drug Discovery ◽  
Drug Design ◽  
Kernel Methods ◽  
Cost Effective ◽  
Activity Relationship ◽  
World Population ◽  
Structure Activity ◽  
The World ◽  
Effective Drugs

Millions of people are suffering from fatal diseases such as cancer, AIDS, and many other bacterial and viral illnesses. The key issue is now how to design lifesaving and cost-effective drugs so that the diseases can be cured and prevented. It would also enable the provision of medicines in developing countries, where approximately 80% of the world population lives. Drug design is a discipline of extreme importance in chemoinformatics. Structure-activity relationship (SAR) and quantitative SAR (QSAR) are key drug discovery tasks.

Pyrazole and imidazo[1,2-b]pyrazole Derivatives as New Potential Antituberculosis Agents

2019 ◽  
Vol 15 (1) ◽  
pp. 17-27 ◽  
Author(s):  
Elda Meta ◽  
Chiara Brullo ◽  
Michele Tonelli ◽  
Scott G. Franzblau ◽  
Yuehong Wang ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Pyrazole Derivatives ◽  
Antitubercular Agents ◽  
Active Compounds ◽  
Protein Targets ◽  
Preliminary Screening ◽  
New Class ◽  
Structure Activity ◽  
Starting Point

Background: We screened a large library of differently decorated imidazo-pyrazole and pyrazole derivatives as possible new antitubercular agents and this preliminary screening showed that many compounds are able to totally inhibit Mycobacterium growth (>90 %). Among the most active compounds, we selected some new possible hits based on their similarities and, at the same time, on their novelty with respect to the pipeline drugs. </P><P> Methods: In order to increase the potency and obtain more information about structure-activity relationship (SAR), we designed and synthesized three new series of compounds (2a–e, 3a–e, and 4a–l). Conclusion: Performed tests confirmed that both new pyrazoles and imidazo-pyrazoles could represent a new starting point to obtain more potent compounds and further work is now underway to identify the protein targets of this new class of anti-TB agents.

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