tyrosyl-tRNA Synthetase Inhibitors Research Articles

Phytochemical and antibacterial analysis of Pistacia integerrima: An integrated in vitro and in silico approach

Antibiotic resistance is a global concern due to the ability of bacteria to continuously develop various mechanisms of resistance against diverse antimicrobial classes; therefore, there is a critical prerequisite to discover diverse antibiotics with novel chemical structures and unique mechanisms of action. The research work aimed to investigate the detailed antibacterial activity and phytochemical characterization of the methanolic extract of Pistacia integerrima galls. Antibacterial properties were analyzed through the well diffusion method and the minimum inhibitory concentration (MIC) was determined through the broth dilution method. MIC of Pistacia integerrima extract (PIE) was found to be 10 mg/mL against both E. coli and S. aureus. Biofilm inhibition was determined by the crystal violet method where PIE demonstrated significant inhibition of biofilms. In the presence of PIE, TEM demonstrated morphological changes in both strains. A total of 17 metabolites were identified through GC-MS analysis with most of the compounds exhibiting antibacterial properties, HPTLC shows the presence of the important metabolite quercetin. Furthermore, virtual ligand screening revealed quercetin and phthalic acid as the most medicinally active constituents and potential inhibitors of tyrosyl-tRNA synthetase (TyrRS) and Dihydrofolate reductase (DHFR). Further research into PIE's bioactive compounds could lead to the development of new antibacterial compounds.

Synthesis, structure elucidation, Hirshfeld surface analysis, DFT, and molecular docking of new 6-bromo-imidazo[4,5-b]pyridine derivatives as potential tyrosyl-tRNA synthetase inhibitors

Novel 6-bromo-imidazo[4,5-b]pyridine derivatives (2-4, 5a-13a, and 6b, 8b-13b) have been synthesized based on a developed systematic approach involving the condensation of 5-Bromo-2,3-diaminopyridine with a suitable aromatic aldehyde in the presence of molecular iodine in water, followed by alkylation reactions using different alkyl dibromide agents. The synthesized compounds were characterized by the NMR spectroscopy technique. The structures of 8a, 9a, 12a, and 11b were confirmed using monocrystalline X-ray crystallography. Theoretical calculations have been carried out using DFT and TD-DFT methods at the B3LYP/6-31G++(d,p) level of theory. Intermolecular contacts between units of 8a, 9a, 12a, and 11b were determined through the Hirshfeld surface analysis. The molecular docking study has been performed to determine the binding affinity of 8a, 9a, 12a, and 11b into the binding site of S. aureus tyrosyl-tRNA synthetase as a target enzyme, and the results revealed that 9a is the most potent compound among the selected compounds with a binding affinity of −8.74 Kcal/mol. Communicated by Ramaswamy H. Sarma

Anti-bacterial efficacy of bio-fabricated silver nanoparticles of aerial part of Moringa oleifera lam: Rapid green synthesis, In-Vitro and In-Silico screening

Silver nanoparticles have been extensively used in pharmaceutical sciences as therapeutic agents, including in drug delivery but their toxicity towards healthy tissue is not explored from trials. Being herb, Moringa oleifera lam (MO) is cheap, eco-friendly, non-toxic as compared to synthetic nanoparticles. The antibacterial efficacy of silver nanoparticles of aerial parts of M. oleifera lam and bactericidal mechanisms have not been explored so far. In this study, rapid biosynthesis of M. oleifera lam embedded silver nanoparticles (MONPs) was acquired using M. oleifera lam aerial parts, and characterized by using UV, Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), and X-ray diffractometer (XRD) studies. Well diffusion method was used to assess the zone of inhibition and minimum inhibitory concentration of the MONPs on Escherichia Coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi . The probable mechanism of action was accessed through molecular docking and simulation. The size of AgNPs was spherical with less than 50 nm size and showed a crystalline peak at XRD. MONPs at 250 μg/ml inhibit the growth of all the gram-positive and gram-negative bacteria with significant antibacterial affinity. The minimum inhibitory concentration of MONPs was lower in gram-positive bacteria than gram-negative bacteria. The molecular docking studies of phytoconstituents present in MO showed luteolin (−9.2 kcal/mol) and rutin (−10.1 kcal/mol) have higher binding energy with DNA gyrase & tyrosyl tRNA synthetase inhibitors respectively. Molecular simulations study confirmed that both ligands have a good stability profile by forming different bonds with active site amino acids. Bio-fabricated silver nanoparticles exhibited noteworthy gainful impacts against selected bacterial strains and could serve as a lead for future antibacterial drug discovery. • Cost effective rapid green synthesis of Moringa olifera (MO) embedded silver nanoparticles. • Antibacterial screening of MO embedded silver nanoparticles showed significant activity against bacteria. • Screening of polyphenolic compounds from MO and docking against bacterial DNA gyrase and tyrosyl tRNA synthetase. • Simulation was performed using rutin and luteolin, these ligands showed highest binding energy with 1kzn and 1jij. • Pharmacokinetics and ADME studies of selected polyphenolic compounds from MO.

Design, synthesis ADMET and molecular docking of new imidazo[4,5-b]pyridine-5-thione derivatives as potential tyrosyl-tRNA synthetase inhibitors

In our effort of discovering new antimicrobial agents, a novel series of imidazo[4,5-b]pyridine-5-thione scaffolds were designed and synthesized and their chemical structures were characterized by physicochemical and spectral analysis. The synthesized compounds were assessed for their in vitro antimicrobial activities against pathogenic microorganisms. Results revealed that out the tested compounds, 3 exhibited the potent inhibitory effect (MIC = 0.49 μg/mL) as compared to the positive control, chloramphenicol (0.98 μg/mL) which predicted also to have the best pharmacokinetic and druglikness properties as well as lower toxicity profiles. Preliminary structure–activity relationships (SARs) study has been also investigated. Moreover, to understand the binding patterns of the tested compounds in the Staphylococcus aureus tyrosyl-tRNA synthetase active site, molecular docking study using the most active compound 3 was carried out. The obtained results indicate that analog 3 can potentially bound to the target enzyme with the highest docking score (−9.37 kcal/mol). Overall, our results showed that antimicrobial activity as well as ADMET and toxicity predictions were in consensus with the docking results.

Novel fused pyridine derivatives containing pyrimidine moiety as prospective tyrosyl-tRNA synthetase inhibitors: Design, synthesis, pharmacokinetics and molecular docking studies

Thirteen fused pyridine derivatives have been designed, synthesized and characterized by 1H NMR, 13C NMR and IR spectral data and elemental analysis. Their in vitro antimicrobial activity was investigated against some pathogenic bacteria and fungi and the majority of them showed excellent to moderate activity, especially compounds 10 and 18 displaying the potent inhibitory effect against K. pneumoniae with MIC values of 2.44 mM and 8.10 mM, respectively. Their pharmacokinetic assessment also revealed promising druglikeness characteristics and ADME properties. The binding interactions of the most active analogues were performed through molecular docking against Staphylococcus aureus tyrosyl-tRNA synthetase. Results revealed that the enhanced activity of compound 10 can be modulated by the establishment, in 10-tyrosyltRNA synthetase complex, of hydrogen bond interactions between the lone pair of sulfur atom of the thiophen-3-amine ring and the hydrogen atom of the hydroxyl group of TYR 170 of 3.80 Å. These findings suggest that analogues 10 and 18 can be served as best candidates for designing and discovering of novel antimicrobial agents.

Synthesis and evaluation of adenosine containing 3-arylfuran-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors

Tyrosyl-tRNA synthetase (TyrRS) is an aminoacyl-tRNA synthetase family protein that possesses an essential role in bacterial protein synthesis. The synthesis, structure-activity relationship, and evolution of a novel series of adenosine-containing 3-arylfuran-2(5H)-ones as TyrRS inhibitors are described. Advanced compound d3 from this series exhibited excellent affinity for TyrRS with IC50 of 0.61 ± 0.04 μM. Bacterial growth inhibition assays demonstrated that d3 showed submicromolar antibacterial potency against Escherichia coli and Pseudomonas aeruginosa, and compared to the marketed antibiotics ciprofloxacin.

C-7 modified flavonoids as novel tyrosyl-tRNA synthetase inhibitors

Twenty C-7 modified flavonoids were designed and synthesized.

Natural Compounds as Inhibitors of Tyrosyl-tRNA Synthetase.

Tyrosyl-tRNA synthetases (TyrRSs) as essential enzymes for all living organisms are good candidates for therapeutic target in the prevention and therapy of microbial infection. We examined the effect of various polyphenols, alkaloids, and terpenes-secondary metabolites produced by higher plants showing many beneficial properties for the human organism, on bacterial aminoacylation reaction. The most potent inhibitors of Escherichia coli TyrRS are epigallocatechin gallate, acacetin, kaempferide, and chrysin, whereas the enzymes from Staphylococcus aureus and Pseudomonas aeruginosa are inhibited mainly by acacetin and chrysin. Most of them act as competitive inhibitors. Structure-activity relationship showed that the most potent flavonoid inhibitors contain hydroxyl group at position 5 and 7 of A ring and OCH3 group at position 4' of B ring.

Metronidazole containing pyrazole derivatives potently inhibit tyrosyl-tRNA synthetase: design, synthesis, and biological evaluation.

As an important enzyme in bacterial protein biosynthesis, tyrosyl-tRNA synthetase (TyrRS) has been an absorbing therapeutic target for exploring novel antibacterial agents. A series of metronidazole-based antibacterial agents has been synthesized and identified as TyrRS inhibitors with low cytotoxicity and significant antibacterial activity, especially against Gram-negative organisms. Of the compounds obtained, 4f is the most potent agent which inhibited the growth of Pseudomonas aeruginosa ATCC 13525 (MIC=0.98μg/mL) and exhibited TryRS inhibitory activity (IC50 =0.92μm). Docking simulation was performed to further understand its potency. Membrane-mediated apoptosis in P.aeruginosa was verified by flow cytometry.

Shikonin derivatives as inhibitors of tyrosyl-tRNA synthetase: design, synthesis and biological evaluation

A series of novel tyrosyl-tRNA synthetase inhibitors was designed and synthesized as anti-bacteria agents based on natural product shikonin and in silico scaffold modification strategy.

Adenosine analogs as inhibitors of tyrosyl-tRNA synthetase: Design, synthesis and antibacterial evaluation

Herein we describe the synthesis and evaluation of a series of adenosine analogs for in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Out of these compounds, compound c6 has much stronger antibacterial potency against Pseudomonas aeruginosa than ciprofloxacin, and was determined to target tyrosyl-tRNA synthetase with IC50 of 0.8±0.07μM. Structure–activity relationship analysis suggested that introduction of a fluorine atom at the 3′-position of benzene ring of the phenylacetyl moiety significantly increased affinities to the enzyme. In comparison with isopropylidene analogs, 2′,3′-deprotected compounds displayed higher inhibitory activity. Molecular dockings provided an explanation for observations in biological assays.

Synthesis and evaluation of new tyrosyl-tRNA synthetase inhibitors as antibacterial agents based on a N2-(arylacetyl)glycinanilide scaffold

Tyrosyl-tRNA synthetase (TyrRS), an essential enzyme in bacterial protein biosynthesis, is an attractive therapeutic target for finding novel antibacterial agents, and a series of N2-(arylacetyl)glycinanilides has been herein synthesized and identified as TyrRS inhibitors. These efforts yielded several compounds, with IC50 in the low micromolar range against TyrRS from Staphylococcus aureus. Out of the obtained compounds, 3ap is the most active and exhibits excellent activity against both Gram-positive (S. aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains. In comparison with the parent scaffold 3-arylfuran-2(5H)-one, N2-(arylacetyl)glycinanilide significantly improved the potency against Gram-negative bacterial strains, indicating that this scaffold offers a significant potential for developing new antibacterial drugs.

4-Hydroxy-3-(naphthalen-1-ylmethyl)thiophen-2(5H)-one as inhibitors of tyrosyl-tRNA synthase: Synthesis, molecular docking and antibacterial evaluation

A series of novel 4-hydroxy-3-(naphthalen-1-ylmethyl)thiophen-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors were synthesized. Of these compounds, 4-(naphthalen-1-ylmethyl)-5-oxo-2,5-dihydrothiophen-3-yl-2-(4-hydroxyphenyl)acetate (29) was the most potent. The binding model and structure–activity relationship indicate that replacement of phenyl acetate in the side chain of 29 with a substituent containing more hydrophilic groups would be more suitable for further modification. Antibacterial assay revealed that the synthetic compounds are effective against growth of Gram-positive organisms, and 29 is the most potent agent against Staphylococcus aureus ATCC 25923 with MIC50 value of 0.21μg/mL.

3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis, molecular docking and antibacterial evaluation

Thirty-eight 3-aryl-4-acyloxyethoxyfuran-2(5H)-ones were designed, prepared and tested for antibacterial activities. Some of them showed significant antibacterial activity against Gram-positive organism, Gram-negative organism and fungus. Out of these compounds, 4-(2-(3-chlorophenylformyloxy)ethoxy)-3-(4-chlorophenyl)furan-2(5H)-one (d40) showed the widest spectrum of activity with MIC50 of 2.0μg/mL against Staphylococcus aureus, 4.3μg/mL against Escherichia coli, 1.5μg/mL against Pseudomonas aeruginosa and 1.2μg/mL against Candida albicans. Our data disclosed that MIC50 values against whole cell bacteria are positive correlation with MIC50 values against tyrosyl-tRNA synthetase. Meanwhile, molecular docking of d40 into S. aureus tyrosyl-tRNA synthetase active site was also performed, and the inhibitor tightly fitting the active site might be an important reason why it has high antimicrobial activity.

Tyrosyl-tRNA synthetase inhibitors as antibacterial agents: Synthesis, molecular docking and structure–activity relationship analysis of 3-aryl-4-arylaminofuran-2(5 H)-ones

Thirty-five 3-aryl-4-arylaminofuran-2(5 H)-one derivatives were designed, prepared and tested for their inhibitory activity against tyrosyl-tRNA synthetase. Out of these compounds, 3-(3-bromophenyl)-4-(3,5-dichlorophenylamino)furan-2(5 H)-one ( 35) was the most active with IC 50 of 0.09 ± 0.02 μM. The structure–activity relationship revealed that introduction of chlorine atoms at both meta positions of aniline moiety significantly increased the enzyme inhibitory activity. The results of antibacterial assay revealed that the tested compounds showed good activity against Gram-positive bacteria, with 35 being the most potent with MIC 50 of 0.06 μg/mL against Staphylococcus aureus ATCC 25923. Molecular docking of 35 into S. aureus tyrosyl-tRNA synthetase active site was also performed. The inhibitor snugly fitting the active site may well explain its excellent inhibitory activity.

4-Alkoxy-3-arylfuran-2(5 H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis, molecular docking and antibacterial evaluation

A series of novel 4-alkoxy-3-arylfuran-2(5 H)-ones as tyrosyl-tRNA synthetase inhibitors were synthesized. Of these compounds, 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5 H)-one ( 27) was the most potent. The binding model and structure–activity relationship indicate that replacement of morpholine-ring in the side chain of 27 with a substituent containing more hydrophilic groups would be more suitable for further modification. Antibacterial assay revealed that the synthetic compounds are effective against growth of Gram-positive organisms, and 27 is the most potent agent against Staphylococcus aureus ATCC 25923 with MIC 50 value of 0.23 μg/mL.

Synthetic analogues of SB-219383. Novel C-glycosyl peptides as inhibitors of tyrosyl tRNA synthetase

Novel inhibitors of bacterial tyrosyl tRNA synthetase have been synthesised in which the cyclic hydroxylamine moiety of SB-219383 is replaced by C-pyranosyl derivatives. Potent and selective inhibition of bacterial tyrosyl tRNA synthetase was obtained.

Potent synthetic inhibitors of tyrosyl tRNA synthetase derived from C-pyranosyl analogues of SB-219383

Novel pyranosyl analogues of SB-219383 have been synthesised to elucidate the structure–activity relationships around the pyran ring. Analogues with highly potent stereoselective and bacterioselective inhibition of bacterial tyrosyl tRNA synthetase have been identified. A major reduction in the overall polarity of the molecule can be tolerated without loss of the nanomolar level of inhibition.