Mayograu4889

Effective treatment of tuberculosis is challenged by the rapid development of Mycobacterium tuberculosis (Mtb) multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor. We previously identified a new class of mycobacterial leucyl-tRNA synthetase inhibitors, N-benzylidene-N'-thiazol-2-yl-hydrazines. Molecular docking of a library of novel N-benzylidene-N'-thiazol-2-yl-hydrazine derivatives into active sites of M. tuberculosis LeuRS (MtbLeuRS) and MetRS (MtbMetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against MtbLeuRS and 28 compounds active against MtbMetRS. The hit compounds display dual inhibitory potency as demonstrated by IC50 values for both enzymes. Compound 3 is active against Mtb H37Rv cells in in vitro bioassays. This journal is © The Royal Society of Chemistry 2019.The biosynthesis of the essential metabolic cofactor coenzyme A (CoA) has been receiving increasing attention as a new target that shows potential to counter the rising resistance to established antimicrobials. In particular, phosphopantothenoylcysteine synthetase (PPCS)-the second CoA biosynthesis enzyme that is found as part of the bifunctional CoaBC protein in bacteria, but is monofunctional in eukaryotes-has been validated as a target through extensive genetic knockdown studies in Mycobacterium tuberculosis. Moreover, it has been identified as the molecular target of the fungal natural product CJ-15,801 that shows selective activity against Staphylococcus aureus and the malaria parasite Plasmodium falciparum. As such, CJ-15,801 and 4'-phospho-CJ-15,801 (its metabolically active form) are excellent tool compounds for use in the development of new antimicrobial PPCS inhibitors. Unfortunately, further study and analysis of CJ-15,801 is currently being hampered by several unique challenges posed by its synthesis. In this study we describe how these challenges were overcome by using a robust palladium-catalyzed coupling to form the key N-acyl vinylogous carbamate moiety with retention of stereochemistry, and by extensive investigation of protecting groups suited to the labile functional group combinations contained in this molecule. We also demonstrate that using TBAF for deprotection causes undesired off-target effects related to the presence of residual tertiary ammonium salts. Finally, we provide a new method for the chemoenzymatic preparation of 4'-phospho-CJ-15,801 on multi-milligram scale, after showing that chemical synthesis of the molecule is not practical. CCT128930 solubility dmso Taken together, the results of this study advances our pursuit to discover new antimicrobials that specifically target CoA biosynthesis and/or utilization. This journal is © The Royal Society of Chemistry 2019.Formyl peptide receptor 1 (FPR1) is expressed on a variety of immune system cells and is a key regulator of the inflammatory environment. Therefore, the development of FPR1 antagonists may represent a novel approach for modulating innate immunity and treating inflammatory diseases. Starting from a dipeptide scaffold that is structurally related to the natural product aurantiamide, we investigated the structure-activity relationships of the dipeptide (2R,2'S)-6, which was reported as an FPR1 antagonist. We found that the absolute configuration 2R,2'S was preferred to obtain potent and selective FPR1 antagonists. The structural modifications performed on the terminal fragments of the molecule suggest that the size of the substituents can greatly influence the interaction with FPR1. These compounds behaved as antagonists in human neutrophils and were able to inhibit formyl peptide-induced chemotaxis. Since FPR1 is a key regulator of the inflammatory environment, the dipeptide derivatives described here may represent important leads for the development of new potent and selective FPR1 antagonists for the treatment of neutrophil-mediated inflammatory diseases. This journal is © The Royal Society of Chemistry 2019.Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and a major cause of death worldwide. The number of people suffering from this debilitating disorder is rising at an unprecedented rate, with a subsequent surge in healthcare costs. Only four drugs are clinically available for the treatment of AD symptoms, but they are not disease-modifying. Consequently, there is an urgent need for a cure. Although the cause of this debilitating condition remains poorly understood, it is believed that several factors may be involved in combination - including, health and lifestyle, environmental, and genetic factors. In recent years, a number of hallmarks of the disease have also been discovered, and it is believed that these factors may play an important role in the development of AD. Amyloid aggregation is one such factor which has been highly investigated, in addition to cholinesterase enzymes and tau aggregation. In the last decade, multi-target drugs have been increasingly investigated for their aeatments for AD. This journal is © The Royal Society of Chemistry 2019.The high storage capacities and excellent biocompatibilities of zinc(ii) metal-organic frameworks (Zn-MOFs) have made them outstanding candidates as drug delivery carriers. Recent studies on the pH-responsive processes based on carrier-drug interactions have proven them to be the most efficient and effective way to control the release profiles of drugs. To satisfy the ever-growing demand in cancer therapy, great efforts are being devoted to the development of methods to precisely control drug release and achieve targeted use of an active substance at the right time and place. In this review article, we discuss the diverse stimuli based on Zn-MOFs carriers that have been achieved upon external activation from single pH-stimulus-responsive or/and multiple pH-stimuli-responsive viewpoints. Also, the perspectives and future challenges in this type of carrier system are discussed. This journal is © The Royal Society of Chemistry 2019.