Molecular docking studies, in-silico ADMET predictions and synthesis of novel PEGA-nucleosides as antimicrobial agents targeting class B1 metallo-β-lactamases (original) (raw)
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Chemical Biology & Drug Design, 2012
Metallo-b-lactamases (MBLs), produced by an increasing number of bacterial pathogens, facilitate the hydrolysis of many commonly used b-lactam antibiotics. There are no clinically useful antagonists against MBLs. Two sets of tetrahydropyrimidine-2-thione and pyrrole derivatives were synthesized and assayed for their inhibitory effects on the catalytic activity of the IMP-1 MBL from Pseudomonas aeruginosa and Klebsiella pneumoniae. Nine compounds tested (1a, 3b, 5c, 6b, 7a, 8a, 11c, 13a, and 16a) showed micromolar inhibition constants (K i values range from 20-80 lM). Compounds 1c, 2b, and 15a showed only weak inhibition. In silico docking was employed to investigate the binding mode of each enantiomer of the strongest inhibitor, 5c (K i = 19 ± 9 lM), as well as 7a (K i = 21 ± 10 lM), the strongest inhibitor of the pyrrole series, in the active site of IMP-1.
The Journal of Organic Chemistry, 2004
Employing an amino acid chiral template strategy, the present research describes a general and highly efficient protocol for the rapid construction of enantiopure furanosyl and pyranosyl nucleoside amino acid cores as present in various complex peptidyl nucleoside antibiotics. Starting from easily available D-serine, the strategy and the approach involve rapid and efficient stereoselective synthesis of five-or six-membered lactone amino alcohols, followed by incorporation of the required functionalities of the target molecules on these strategically functionalized chiral templates.
European Journal of Medicinal Chemistry, 2011
There are currently no clinically useful inhibitors against metallo-b-lactamases (MBLs), enzymes that confer resistance against a broad spectrum of commonly used antibiotics and that are produced by an increasing number of bacterial pathogens. New pyrrole derivatives were synthesized and assayed for their inhibitory effect on the catalytic activity of the IMP-1 MBL from Pseudomonas aeruginosa and Klebsiella pneumoniae. Six compounds tested (3a-3c, 5, 7 and 8) show micromolar inhibition constants (K i values range from w10 to 30 mM). In silico docking was employed to investigate the binding mode of the strongest inhibitor, 3b, in the active site of IMP-1. Implications for further improvements of binding efficiency and specificity are discussed.
European Journal of …, 2011
There are currently no clinically useful inhibitors against metallo-b-lactamases (MBLs), enzymes that confer resistance against a broad spectrum of commonly used antibiotics and that are produced by an increasing number of bacterial pathogens. New pyrrole derivatives were synthesized and assayed for their inhibitory effect on the catalytic activity of the IMP-1 MBL from Pseudomonas aeruginosa and Klebsiella pneumoniae. Six compounds tested (3a-3c, 5, 7 and 8) show micromolar inhibition constants (K i values range from w10 to 30 mM). In silico docking was employed to investigate the binding mode of the strongest inhibitor, 3b, in the active site of IMP-1. Implications for further improvements of binding efficiency and specificity are discussed.
Nucleoside–amino acid conjugates: An alternative route to the design of ribonuclease A inhibitors
Bioorganic & Medicinal Chemistry, 2009
Nucleoside-amino acid conjugates have been employed to inhibit the ribonucleolytic activity of ribonuclease A (RNase A) and affect the protonation/deprotonation equilibrium of its active site histidine residues. Agarose gel and precipitation assays indicate inhibition of RNase A activity by these molecules with a possible role of the polar side chains of the amino acids in RNase A inhibition. Kinetic experiments demonstrated that the mode of inhibition is competitive in nature with inhibition constants (K i) in the micromolar range. The nucleoside-serine conjugate occupies the active site of RNase A and preferential perturbs the pK a value of His-119 by its 'free amino group' as found from 1 H NMR studies. Docking studies revealed that the free amino groups of the most active compounds are within hydrogen bonding distance of His-119 in inhibitor-RNase A complexes.
Antimicrobial metallopeptides with broad nuclease and ribonuclease activity
Chemical Communications, 2013
Metallopeptides containing both the complex Cu 2+-glycyl-glycyl-histidine (Cu-GGH) and the sequence WRWYCR were shown to possess antimicrobial activity against a variety of pathogenic bacteria, as well as bind to and cleave a variety of nucleic acids, suggesting potential mechanisms for antimicrobial activity that involve binding and/or irreversible cleavage of bacterial nucleic acids. Current major classes of antimicrobial agents include β-lactams, aminoglycosides, macrolides, tetracyclines, fluoroquinolones, and various peptides, 1-3 with the evolution of drug-resistance in pathogenic bacteria as a rising concern. 4-7 The most widely used modes of action include inhibition of protein biosynthesis and cell wall formation through binding of ribosomal RNA and proteins involved in cell wall synthesis, respectively. 8 Since nucleic acids (both DNA and RNA) mediate many critical cellular processes that include the storage, transmission, and translation of genetic information, binding of specific nucleic acid targets has been a common mechanism of action employed by many antibiotics. However, to date, strikingly few of the vast number of potential nucleic acid targets in bacteria have been exploited. Due to the rise of bacterial drug-resistance there is a clear general need for new antibiotics that function on distinct targets and through novel modes of action. Recent work demonstrated antimicrobial activity for peptide WRWYCR. 2 The activity of this peptide was ascribed to binding and trapping of bacterial Holliday junctions (HJ DNA) that arise during homologous recombination, a fundamental cellular process. 1, 2, 9 Herein we investigate the antimicrobial activity, nucleic acid binding, and nucleolytic properties of peptide WRWYCR-NH 2 , as well as derivative metallopeptides containing both the catalytically active N-terminal complex Cu 2+-GlyGlyHis (Cu-GGH) 10-20 and the WRWYCR targeting peptide, and test for antimicrobial activity against various pathogens (Table 1). The metallopeptides had favorable bacteriocidal activity, with minimal inhibitory concentrations in the low micromolar range (Table 1) and K D values for DNA-and RNA
Pharmacia, 2021
Nucleoside derivatives are important therapeutic drugs and are the focal point in the ongoing search for novel, more potent drug targets. In this study, a new series of pyrimidine nucleoside i.e., uridine (1) derivatives were synthesized via direct method and evaluated for their antimicrobial potential activity. The title compound uridine (1) was treated with triphenylmethyl chloride in pyridine to give the 5´-O-(triphenylmethyl)uridine derivative (2), which was subsequently derivatized to create a series of 2´,3´-di-O-acyl analogs containing a wide variety of functionalities in a single molecular framework. In vitro antimicrobial functionality tests were determined against both human and plant pathogens by disc diffusion and food poisoned techniques. The chemical structures of the synthesized compounds were confirmed on the basis of their spectral, analytical, physicochemical data. The antimicrobial results indicated that the synthesized derivatives exhibited moderate to good antib...
Medicinal Chemistry Research, 2011
A series of the novel pyrimidine (3-6) and purine (12)(13)(14)(15)(18)(19)(20)(21) acyclic nucleoside analogues in which the sugar moiety was replaced by a sterically constrained Z-4-amino-, 4-aminohydrochloride-2-butenyl, or aliphatic 4-aminohydrochloride-2-butyl moiety were synthesized and evaluated for their anti-viral and cytostatic activity potency. Cytostatic evaluation of the novel compounds on selected panel of human tumour-cell lines showed that the majority of compounds exerted a nonspecific anti-proliferative effect at the highest tested concentration (i.e. 1 9 10 -4 M) against all cell lines. Nevertheless, a rather moderate but selective anti-proliferative effects on HeLa cell cultures in comparison to normal fibroblasts WI 38, were observed for compounds 15 and 21. No anti-viral activity was observed, except for compounds 3, 4, 5 and 19 that showed anti-HIV activity at 50% effective concentration ranging between 10 and 96 lM. MEDICINAL CHEMISTRY RESEARCH 1.82 (td, 2H, J 3 = 7.23) 1.46 (td, 2H, J 3 = 7.95) 1.95 (t, 2H, J 3 = 7.50) 1.56 (t, 2H, J 3 = 7.11) 2.81 (d, 2H, J
Synthesis and biological evaluation of novel β-lactam-metallo β-lactamase inhibitors
RSC Advances, 2023
b-lactamases are enzymes that deactivate b-lactam antibiotics through a hydrolysis mechanism. There are two known types of b-lactamases: serine b-lactamases (SBLs) and metallo b-lactamases (MBLs). The two existing strategies to overcome b-lactamase-mediated resistance are (a) to develop novel b-lactam antibiotics that are not susceptible to hydrolysis by these enzymes; or (b) to develop b-lactamase inhibitors that deactivate the enzyme and thereby restore the efficacy of the co-administered antibiotics. Many commercially available SBL inhibitors are used in combination therapy with antibiotics to treat antimicrobial resistant infections; however, there are only a handful of MBL inhibitors undergoing clinical trials. In this study, we present 11 novel potential MBL inhibitors (via multi-step chemical synthesis), that have shown to completely restore the efficacy of meropenem (#2 mg L −1) against New Delhi metallo-b-lactamase (NDM) producing Klebsiella pneumoniae in vitro. These compounds contain a cyclic amino acid zinc chelator conjugated to various commercially available b-lactam antibiotic scaffolds with the aim to improve the overall drug transport, lipophilicity, and pharmacokinetic/pharmacodynamic properties as compared to the chelator alone. Biological evaluation of compounds 24b and 24c has further highlighted the downstream application of these MBLs, since they are non-toxic at the selected doses. Time-kill assays indicate that compounds 24b and 24c exhibit sterilizing activity towards NDM producing Klebsiella pneumoniae in vitro using minimal concentrations of meropenem. Furthermore, 24b and 24c proved to be promising inhibitors of VIM-2 (K i = 0.85 and 1.87, respectively). This study has revealed a novel series of b-lactam MBLIs that are potent, efficacious, and safe leads with the potential to develop into therapeutic MBLIs. cantly to antibiotic resistance. 1,3,4 The Antimicrobial Resistance (AMR) National Strategy Framework (2018-2024), as well as the Global Research and Development priority setting for AMR, and the Global Antibiotic Research and Development Partnership, prioritise research regarding antimicrobial treatment to help prevent obsolete antibiotics emanating as a result of mutations and bacterial evolution. 5-7 Antibiotic resistance has worsened, due to the empirical treatment of hospitalised COVID-19 patients. 3,8,9 There are several initiatives in place to either raise awareness, help reduce, or keep track of resistance, such as: the Global Action Plan on Antimicrobial Resistance (GAP); World Antimicrobial Awareness Week (WAAW); The Global Antimicrobial Resistance and Use Surveillance System (GLASS); Global Research and Development priority setting for AMR; Access Watch Reserve (AWaRe); and Global Antibiotic Research and Development Partnership (GARDP). 7 Murray et al. estimated that 4.95 million deaths occurred in the year 2019 as a result of antibiotic resistance. 6 Identied Klebsiella pneumoniae, as a common pathogen accounting for 29% of all reported bacterial infections. 7 Klebsiella pneumoniae has recently been identied as a bacteria of concern, as mentioned in several reports, studies, and reviews, and is further substantiated by the resistance map (Fig. 1) generated from the CDDEP (Centre for Disease Dynamics, Economics and Policy). 10 Unfortunately,