MurB Enzyme Research Articles

Elucidating the antimicrobial and anticarcinogenic potential of methanolic and water extracts of edible Tragopogon coelesyriacus Boiss.

Tragopogon coelesyriacus is a pharmacotherapeutic herbaceous plant belonging to the Asteraceae family and consumed as a vegetable. Here, the methanolic and water extracts of T. coelesyriacus were obtained from its aboveground parts (stem, leaves, and flowers), and the phytochemical potentials were investigated by LC-HRMS (liquid chromatography-high resolution mass spectrometry) analysis for the first time. The antibacterial, antifungal, and anticarcinogenic activities of T. coelesyriacus extracts were investigated using experimental and in silico methods. T. coelesyriacus methanol extract revealed remarkable inhibitory activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumonia (MICs = 0.83, 1.67, and 1.67 mg/mL, respectively) compared to Escherichia coli and Enterobacter aerogenes (MIC = 53.3 mg/mL). Inhibitory effects of T. coelesyriacus methanolic extracts were also observed in all Candida species tested, with the highest inhibition on Candida krusei (MIC = 0.83 mg/mL), whereas no inhibitory effect was identified from the water extract. Additionally, both T. coelesyriacus methanolic (IC50 = 86 μg/mL) and water (IC50 = 92 μg/mL) extracts revealed significant selective anticarcinogenic effects on AR42J pancreatic cancer cells. HeLa and MDA-MB-231 cells were, however, more resilient to methanol and water extract, respectively. In silico analyses further elucidated the noteworthy antibacterial potential of keracyanin chloride on S. aureus MurB enzyme and the remarkable inhibitory potential of naringin on FYN kinase specific for pancreatic cancer (AR42J) development. In conclusion, T. coelesyriacus phytochemicals with antibacterial, antifungal, and anticancer properties were revealed for the first time, and molecular docking studies on potential targets confirmed good agreement with experimental findings. Therefore, the current studies on T. coelesyriacus provide the basis for investigating new pharmaceutical potentials of other Tragopogon members.

New 1H-1,2,4-Triazolyl Derivatives as Antimicrobial Agents.

New 1H-1,2,4-triazolyl derivatives were synthesized, and six of them were selected based on docking prediction for the investigation of their antimicrobial activity against five bacterial and eight fungal strains. All compounds demonstrated antibacterial activity with MIC lower than that of the ampicillin and chloramphenicol. In general, the most sensitive bacteria appeared to be P. fluorescens, while the plant pathogen X. campestris was the most resistant. The antifungal activity of the compounds was much better than the antibacterial activity. All compounds were more potent (6 to 45 times) than reference drugs ketoconazole and bifonazole with the best activity achieved by compound 4 a. A. versicolor, A. ochraceus, A.niger, and T.viride showed the highest sensitivity to compound 4 b, while, T. viride, P. funiculosum, and P.ochrochloron showed good sensitivity to compound 4 a. Molecular docking studies suggest that the probable mechanism of antibacterial activity involves the inhibition of the MurB enzyme of E. coli, while CYP51 of C. albicans appears to be involved in the mechanism of antifungal activity. It is worth mentioning that none of the tested compounds violated Lipinski's rule of five.

Targeting MurB from Helicobacter pylori: insights from virtual screening, molecular docking and molecular dynamics simulation

ABSTRACT Helicobacter pylori is a gram-negative, helical-shaped bacteria found in the mucus lining of the stomach of humans responsible for causing sores or an ulcer. H. pylori is becoming a multi-drug resistant bacterium, which in turn demands the need for development of alternative treatment strategies for the proper management of diseases. The peptidoglycan biosynthesis pathway is critical for the synthesis of cell walls and for the survival of H. pylori. There are several crucial enzymes in this biosynthesis pathway which can act as significant drug targets against H. pylori. One of these important enzymes is UDP-N-acetylenolpyruvoylglucosamine reductase (MurB), which catalyses an important committed step of cell wall biosynthesis. In the present study, we performed a high throughput virtual screening using the Enamine HTSC library against the MurB enzyme. The molecules were also screened for druglike properties by ADME screening, toxicity, and tumorigenic nature, followed by MD simulations. We found that Z102621114_1 and Z228235240_1 ligand molecules can act as potential inhibitors of MurB protein. Our results suggest, these molecules may be able to meet the demand for novel antimicrobials to treat H. pylori medication resistance. The subsequent experimental investigations can increase their potential as a novel agents against H. pylori infections. Research highlights Helicobacter pylori infects 50% of the Global population. Helicobacter pylori infection is associated with gastric cancer. MurB is a key drug target protein as it is responsible for cell wall synthesis. Z102621114_1 and Z228235240_1 were identified as potential inhibitors of MurB of Helicobacter pylori.

Tannin derived from Uncaria gambir Roxb. as potential Enterococcus faecalis UDP-N-Acetylenolpyruvoyl-Glucosamine Reductase (Mur Benzyme) inhibitor: In-silico antibacterial study

The high prevalence of pulp and periapical disease is an important problem for dental and oral health in dentistry. Treatment of pulp and periapical disease is generally carried out utilizing root canal treatment, but the results of the treatment are often not as expected. Enterococcus faecalis is a bacterium that plays a role in the failure of root canal treatment. E. faecalis are Gram-positive bacteria that use the Muramidase B (MurB) enzyme in the biosynthesis of peptidoglycan, which will build bacteria cell walls and play an important role in protecting bacteria. Gambir (Uncaria gambir Roxb.) is an herbal plant that is used in the field of medicine and contains tannin compounds that have antibacterial activity. The purpose of this study was to predict the antibacterial activity of Gambir extracts against the MurB enzyme compared with chlorhexidine through in silico approach. The Mur B enzyme was obtained from the Protein Data Bank (PDB), and the structure of the compound (tannins and chlorhexidine) was obtained from Pubchem. Using Auto dock tools from Pyrx software for docking between the two compounds (tannin and chlorhexidine) with the MurB enzyme, and visualize using Pymol and 3D analysis using Biovia. The results showed that tannins had a binding affinity of more than -7.4 kcal.mol-1 to the MurB enzyme and chlorhexidine had a higher binding affinity than tannins. Both tannins and chlorhexidine have hydrogen bonds with the same three amino acids, that is ARG 159, GLY 123, and ASN 233. The results showed that tannins interacted with the MurB enzyme and could inhibit the action of the MurB enzyme.

Screening and molecular dynamics simulation of compounds inhibiting MurB enzyme of drug-resistant Mycobacterium tuberculosis: An in-silico approach

Mycobacterium tuberculosis (MTB) is becoming more and more resistant to drugs and it is a common problem, making current antimicrobials ineffective and highlighting the need for new TB drugs. One of the promising targets for treating MTB is MurB enzymes. This study aimed to identify potential inhibitors of MurB enzymes in M. tuberculosis, as drug resistance among MTB is a significant problem. Attempts are being made to conduct a virtual screening of 30,417 compounds, and thirty-two compounds were chosen for further analysis based on their binding conformations. The selected compounds were assessed for their drug-likeness, pharmacokinetics, and physiochemical characteristics, and seven compounds with binding energy lower than flavin (FAD) were identified. Further, molecular dynamics simulation analysis of these seven compounds found that four of them, namely DB12983, DB15688, ZINC084726167, and ZINC254071113 formed stable complexes with the MurB binding site, exhibiting promising inhibitory activity. These compounds have not been mentioned in any other study, indicating their novelty. The study suggests that these four compounds could be promising candidates for treating MTB, but their effectiveness needs to be validated through in vitro and in vivo experiments. Overall, the findings of this study provide new insight into potential drug targets and candidates for combating drug-resistant MTB.

A rhodanine derivative as a potential antibacterial and anticancer agent: Crystal structure, spectral characterization, DFT calculations, Hirshfeld surface analysis, in silico molecular docking and ADMET studies

A novel rhodanine derivative, namely 5-(4-dimethylaminobenzylidene) rhodanine “C12H12N2OS2”, was successfully crystallized from condensation route and characterized by NMR, FT-IR, UV–Vis spectral methods as well as single-crystal X-ray diffraction. This rhodanine derivate crystallizes in the monoclinic P21/c space group, with the cell parameters: a = 3.93590(10), b = 11.2480(3), c = 26.6703(7) Å and β = 93.8530(10)°. The molecular structure displays intra- (C − S···H) and intermolecular (N − H···O) hydrogen-bonding interactions. Micro-spectroscopy performed on single-crystals of the studied compound revealed the first absorption transition at 2.25 eV, and a well-structured luminescence peaked at 2.01 eV (0.15 eV broad). Density functional theory (DFT) calculations allowed the structure optimization, the electronic properties, the IR-vibrational modes and frequencies as well as the 1H and 13C NMR chemical shifts’ calculation. Furthermore, time-dependent DFT (TD-DFT) calculations were performed for the vertical transition energies. Hirshfeld surface analysis (HSA) showed the presence of non-conventional C–H···H–C, C–H···π and π···lp interactions and π−π stacking. The anti-cancer and anti-bacterial activities of the studied compound towards the Polo-like kinase PLK1 and the Escherichia coli MurB enzymes were in silico evaluated by performing molecular docking simulations. The results suggest that the molecule can significantly inhibit the enzymes’ active sites. Additionally, the physicochemical and pharmacokinetic characteristics of the molecule were evaluated through absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis, and the results ensure its good drug-likeness properties.

Synthesis and Antimicrobial Activity of New Heteroaryl(aryl) Thiazole Derivatives Molecular Docking Studies.

Herein, we report the design, synthesis, and evaluation of the antimicrobial activity of new heteroaryl (aryl) thiazole derivatives. The design was based on a molecular hybridization approach. The in vitro evaluation revealed that these compounds demonstrated moderate antibacterial activity. The best activity was achieved for compound 3, with MIC and MBC in the range of 0.23-0.7 and 0.47-0.94 mg/mL, respectively. Three compounds (2, 3, and 4) were tested against three resistant strains, namely methicillin resistant Staphylococcus aureus, P. aeruginosa, and E. coli, which showed higher potential than the reference drug ampicillin. Antifungal activity of the compounds was better with MIC and MFC in the range of 0.06-0.47 and 0.11-0.94 mg/mL, respectively. The best activity was observed for compound 9, with MIC at 0.06-0.23 mg/mL and MFC at 0.11-0.47 mg/mL. According to docking studies, the predicted inhibition of the E. coli MurB enzyme is a putative mechanism of the antibacterial activity of the compounds, while inhibition of 14a-lanosterol demethylase is probably the mechanism of their antifungal activity.

Synthesis, biological evaluation, and molecular docking studies of thiazolo[4,5‐b]pyridin‐5‐ones as antimicrobial agents

AbstractHerein we report the design and synthesis of thiazolo[4,5‐b]pyridin‐5‐ones and evaluation of their antimicrobial activity. The design was based on a molecular hybridization approach. Evaluation of their antibacterial activity revealed that these compounds generally showed moderate antibacterial activity. The best activity was achieved for compound 4p with MIC/MBC in the range of 0.12–0.47 and 0.23–0.94 mg mL−1 respectively. Three compounds (4g, 4n, and 4p) were tested against three resistant strains, namely MRSA, p.aeruginosa, and E.coli, showing higher inhibition potential than the reference drug ampicillin. These three compounds also were tested for their ability to inhibit biofilm formation, with two of them showing better activity than streptomycin in a concentration of MIC (4p) and ampicillin in both concentrations (MIC and 0.5 MIC). As far as antifungal activity is concerned, the best activity was observed for compound 4i with MIC at 0.12–0.47 mg mL−1 and MFC at 0.23–0.94 mg m−1. According to docking studies, the predicted inhibition of E.coli MurB enzyme is probably a putative mechanism of the antibacterial activity of these compounds, while inhibition of 14a‐lanosterol demethylase is probably the mechanism of their antifungal activity.

Mode action prediction of catechin from Uncaria gambir Roxb. against UDP-N-acetylenolpyruvyl-glucosamine reductase (MurB enzyme) of Streptococcus mutans: In silico study.

ABSTRACTThe prevalence of oral health problems in the global population is still high, especially dental caries, which is considered a multifactorial disease involving the role of bacteria, namely Streptococcus mutans. Gram-positive bacteria metabolize carbohydrates and sugars and convert them into lactic acid, causing dental caries. The peptidoglycan (PG) layer at the outer surface of the bacteria acts as protection. MurB enzyme is known for its contribution to PG biosynthesis. Gambir (Uncaria gambir Roxb.) is famous for many efficacies. Previous studies show that catechin from herb plants such as U. gambir has antibacterial activity. This study aimed to evaluate and predict the antibacterial activity of catechin from U. gambir against the MurB enzyme, which contributes to forming the bacteria PG, with an in silico approach. The structure of the MurB enzyme was collected from UniProt, and the ligands (catechin and chlorhexidine) structures were obtained from PubChem. The AutoDock software was used to dock both ligand and MurB enzyme visualized using PyMOL and analyzed using BIOVIA. The results showed that catechin has a binding affinity of more than − 7 kcal/mol against the MurB enzyme, and chlorhexidine has a higher binding affinity than catechin. Both catechin and chlorhexidine have similar amino acids attachment by hydrogen bonds. The results showed that catechin has competitive antibacterial activity against chlorhexidine in inhibiting the MurB enzyme.

Utility of pyrrole‐2‐thioacetohydrazide in synthesis of new heterocyclic compounds with promising antimicrobial activities and molecular docking studies

AbstractOne‐pot synthetic method for [(3‐cyano‐5‐phenyl‐1H‐pyrrol‐2‐yl)sulfanyl]acetic acids 3a,b with excellent yield have been accomplished via a tetrabutylammonium bromide (TBAB) catalyzed reaction of mercaptoacetic acid with 2‐(2‐oxo‐2‐arylethyl) malononitrile under phase transfer catalysis conditions (PTC). The coupling of methyl [(3‐cyano‐5‐phenyl‐1H‐pyrrol‐2‐yl)sulfanyl] acetate 4a,b with hydrazine gave the corresponding 2‐[(3‐cyano‐5‐aryl‐1H‐pyrrol‐2yl)thio] acetohydrazides 5a,b, which reacted with glucose, acetylacetone, carbon disulfide, phenyl isothiocyanate, chloroacetyl chloride or benzaldehyde, to afford the compounds 6a,b–11a,b, respectively ranged from satisfactory to excellent yields. In vitro antibacterial and antifungal activities were assessed with good results. Furthermore, molecular docking experiments were done for the most active compounds against the E. coli MurB enzyme in order to determine the mechanism of their antibacterial activity and showed good binding interactions.

Synthesis, in silico studies and antibacterial assessment of α-amino phosphonates derivatives

The widespread of multi-resistant strains due to the lack of specific treatment and the propagation of infectious diseases requires all resources to remedy this scourge. This study is therefore aimed to assess the antibacterial activity of four synthetic α-Aminophosphonate 4(a-d). Methods: Firstly, α-Aminophosphonate has been synthesized and characterized, then molecular docking of these compounds 4(a-d) into the active binding site of Escherichia coli MurB enzyme (PDB Id: 1MBT) was performed to gain a comprehensive understanding of their biological activity. These compounds have been subjected to in vitro antibacterial screening against three multi-resistant strains E. coli, S. aureus, and L. monocytogenes. These compounds showed crucial antibacterial behavior against all studied strains. Thus, their docking estimation supported the in vitro results and showed that the 4c derivative has considerable binding energy towards the active site of Escherichia coli MurB. These findings provide critical information for the exploration of α-amino phosphonates as novel antibacterial agents.

A comparative study of different docking methodologies to assess the protein–ligand interaction for the E. coli MurB enzyme

We have investigated the active site of E. coli MurB using the Quantum Mechanics/Molecular Mechanics (QM/MM) methodology. The docking of three novel series of 4-thiazolidinone derivatives has been performed using two methods: rigid docking and flexible docking (Induced Fit Docking: IFD). The results have been compared to understand the conformational aspects of the enzyme. The docking results from rigid docking show that the ligands with highly negative ΔGbind have poor docking scores. In addition, the value of the regression coefficient (R) obtained on correlating the ΔGbind and the experimental pMIC values is insignificant. On keeping the protein flexible, there is a remarkable improvement in both the docking score and ΔGbind , along with a good value of R (0.64). Two important residues, Tyr254 and Try190 are found to be highly displaced during the flexible docking and hence their role in effective ligand binding has been confirmed. Thus, comparing the two methodologies, IFD has emerged as the more appropriate one for studying the E. coli MurB enzyme. To further substantiate the findings, MD studies over a time period of 20 ns have been performed on the IFD-LIII j and Rigid/XP-LIII j complexes and the results shows the former complex to be more stable, with lower average RMSD and higher average ΔGbind. Communicated by Ramaswamy H. Sarma

Crystal structures of UDP-N-acetylmuramic acid L-alanine ligase (MurC) from Mycobacterium bovis with and without UDP-N-acetylglucosamine.

Peptidoglycan comprises repeating units of N-acetylmuramic acid, N-acetylglucosamine and short cross-linking peptides. After the conversion of UDP-N-acetylglucosamine (UNAG) to UDP-N-acetylmuramic acid (UNAM) by the MurA and MurB enzymes, an amino acid is added to UNAM by UDP-N-acetylmuramic acid L-alanine ligase (MurC). As peptidoglycan is an essential component of the bacterial cell wall, the enzymes involved in its biosynthesis represent promising targets for the development of novel antibacterial drugs. Here, the crystal structure of Mycobacterium bovis MurC (MbMurC) is reported, which exhibits a three-domain architecture for the binding of UNAM, ATP and an amino acid as substrates, with a nickel ion at the domain interface. The ATP-binding loop adopts a conformation that is not seen in other MurCs. In the UNAG-bound structure of MbMurC, the substrate mimic interacts with the UDP-binding domain of MbMurC, which does not invoke rearrangement of the three domains. Interestingly, the glycine-rich loop of the UDP-binding domain of MbMurC interacts through hydrogen bonds with the glucose moiety of the ligand, but not with the pyrophosphate moiety. These findings suggest that UNAG analogs might serve as potential candidates for neutralizing the catalytic activity of bacterial MurC.

Novel bis(pyrazole-benzofuran) hybrids possessing piperazine linker: Synthesis of potent bacterial biofilm and MurB inhibitors

Novel 1,4-bis[(2-(3-(dimethylamino)-1-oxoprop-2-en-1-yl)benzofuran-5-yl)methyl]piperazine was prepared and used as a key synthon for the this study. Therefore, 1,3-dipolar cycloaddition of this synthon with the appropriate hydrazonyl chlorides afforded a new series of bis(1,3,4-trisubstituted pyrazoles), linked via piperazine moiety. Furthermore, it reacted with hydrazine hydrate and phenyl hydrazine individually to afford the corresponding 1,4-bis[(2-(1H-pyrazolyl)benzofuran-5-yl)methyl]piperazines. Different bacterial strains and cell lines were selected to study the in-vitro antibacterial and cytotoxic activities for the new derivatives. 1,4-Bis[((2-(3-acetyl-1-(4-nitrophenyl)-1H-pyrazole-4-yl)carbonyl)benzofuran-5-yl)methyl]piperazine 5e showed the best antibacterial efficacies with MIC/MBC values of 1.2/1.2, 1.2/2.4 and 1.2/2.4 μM against each of E. coli, S. aureus and S. mutans strains, respectively. In addition, the inhibitory activity of some new bis(pyrazoles) as MRSA and VRE inhibitors were studied. Compound 5e gave the best inhibitory activity with MIC/MBC values of 18.1/36.2, 9.0/18.1 and 18.1/18.1 µM, respectively, against MRSA (ATCC:33591 and ATCC:43300) and VRE (ATCC:51575) bacterial strains, respectively. Compound 5e showed more effective biofilm inhibition activities than the reference Ciprofloxacin. It showed IC50 values of 3.0 ± 0.05, 3.2 ± 0.08 and 3.3 ± 0.07 μM against S. aureus, S. mutans and E. coli strains, respectively. Furthermore, experimental study showed excellent inhibitory activities of 1,4-bis[((2-(3-substituted-1-aryl-1H-pyrazole-4-yl)carbonyl)benzofuran-5-yl)methyl]piperazine derivatives, attached to p-NO2 or p-Cl groups, against MurB enzyme. Compound 5e gave the best MurB inhibitory activity with IC50 value of 3.1 μM. The in-silico study was performed to predict the capability of new derivatives as potential inhibitors of MurB enzyme.

Synthesis, Antimicrobial and Molecular Modeling Studies of Some Benzophenone-based Thiazole and 4-Thiazolidinone Derivatives

New series of thiazolyl hydrazones were designed and synthesized via the reaction of benzophenone thiosemicarbazone 2 with chloroacetic acid, (un)substituted phenacylbromide and ethyl-2-chloroacetoacetate to yield compounds 3, 5a-d & 6 respectively. Furthermore, reaction of the thiazolidin-4-one 3 with aromatic aldehydes afforded compounds 4a-g. Characterization data, along with in vitro antimicrobial activity for all compounds are herein reported. All the synthesized compounds were screened against Methicillin- Resistant Staphylococcus aureus (MRSA), E. coli, K. pneumonia, P. aeruginosa, A baumannii, C. albicans and C. neoformans var.grubii. Compounds 2 and 4e showed the highest bacterial growth inhibition with 28.6% and 28.7% against MRSA, respectively. Moreover, the trisubstituted thiazole derivative 6 was the most active compound against Gram-negative bacteria A. baumannii with 59% growth inhibition. Furthermore, compounds 4e & 6 showed 22.5% and 17.3% decrease in peptidoglycan density, respectively. Molecular docking into bacterial MurB enzyme active site was used to determine their binding modein which they showed good interactions with Gln229, Arg225 and Ser82 amino acid residues.

Synthesis of novel 1,2-diarylpyrazolidin-3-one-based compounds and their evaluation as broad spectrum antibacterial agents.

There is a continuous need to develop new antibacterial agents with non-traditional mechanisms to combat the nonstop emerging resistance to most of the antibiotics used in clinical settings. We identified novel pyrazolidinone derivatives as antibacterial hits in an in-house library screening and synthesized several derivatives in order to improve the potency and increase the polarity of the discovered hit compounds. The oxime derivative 24 exhibited promising antibacterial activity against E. coli TolC, B. subtilis and S. aureus with MIC values of 4, 10 and 20µg/mL, respectively. The new lead compound 24 was found to exhibit a weak dual inhibitory activity against both the E. coli MurA and MurB enzymes with IC50 values of 88.1 and 79.5µM, respectively, which could partially explain its antibacterial effect. A comparison with the previously reported, structurally related pyrazolidinediones suggested that the oxime functionality at position 4 enhanced the activity against MurA and recovered the activity against the MurB enzyme. Compound 24 can serve as a lead for further development of novel and safe antibiotics with potential broad spectrum activity.

Design, synthesis, molecular docking, and biological evaluation of novel selenium containing lumefantrine analogues

AbstractA new series of 1‐(9‐benzylidene‐2,7‐dichloro‐9H‐fluoren‐4‐yl)‐2‐(methylselanyl)ethanol was synthesized by a simple Knoevenagel condensation of 1‐(2,7‐dichloro‐9H‐fluoren‐4‐yl)‐2‐(methylselanyl)ethanol with different substituted aromatic aldehydes in basic media. These synthesized compounds were confirmed on the basis of their elemental analyses, infrared (IR), 1H NMR, 13C NMR, and mass spectral data and screened for the antibacterial and antifungal activity. The preliminary antibacterial and antifungal screening revealed that the compounds 8c (dichloro), 8d (fluoro), 8e (chloro), 8i (methoxy), and 8l (methyl) displayed moderate to good activity. The antibacterial results of these compounds were further supported by in silico molecular docking studies, for the inhibition of Escherichia coli MurB enzyme (PDB code: 2MBR), wherein they showed higher binding energy and good affinity towards the active pocket of the enzyme compared with that of the standard drug Ciprofloxacin. Thus, the plausible mechanism of their antibacterial activity was owed to their inhibitory action of the bacterial MurB enzyme.

Structure-based virtual screening, free energy of binding and molecular dynamics simulations to propose novel inhibitors of Mtb-MurB oxidoreductase enzyme

Currently, the growing incidence of drug resistance toward tuberculosis intensified the need for discovery of novel targets and their inhibitors. The enzyme MurB which is involved in one of the steps for peptidoglycan biosynthesis is an effective target that can produce drugs having lesser side-effects. Recently the only crystal structure of Mycobacterium Tuberculosis MurB has been deposited and, therefore, in the present study, we have used this as a target for virtual screening of drug-like molecules from the ZINC Database. We have also designed a complete workflow for the process which resulted in 12 hit compounds that have good docking scores, ΔGbind, and Glide energy. The hits obtained have also been found to share structural features with some known antibiotics such as Amoxicillin. Furthermore, MD simulations on the top most hit L1 displayed its stable binding with the enzyme. Thus, this study has proved helpful in proposing novel inhibitors for MurB enzyme that can be tested against various TB strains.

Synthesis, in-vitro and in-silico study of novel thiazoles as potent antibacterial agents and MurB inhibitors.

Efficient procedures are herein reported for the synthesis of novel hybrid thiazoles via a one-pot three-component protocol. The protocol involves the reaction of novel aldehyde, thiosemicarbazide and halogen-containing reagents in solvent- and catalyst-free conditions. The structures of the new thiazoles were elucidated by elemental analyses and spectroscopic data. The in-vitro antibacterial screening and MurB enzyme inhibition assays were performed for the novel thiazoles. The thiazol-4(5H)-one derivative 6d, with p-MeO, exhibits the best antibacterial activities with minimum inhibitory concentration values of 3.9, 3.9, 7.8, and 15.6 μg/ml against Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus mutans, and Escherichia coli, respectively, as compared to the reference antibiotic drugs. It also exhibits the highest inhibition of the MurB enzyme with an IC50 of 8.1 μM. The structure-activity relationship was studied to determine the effect of the structures of the newly prepared molecules on the strength of the antibacterial activities. Molecular docking was also performed to predict the binding modes of the new thiazoles in the active sites of the E. coli MurB enzyme.

Design, Synthesis, Antimicrobial Evaluation and Molecular Modeling Study of 1,2,4-Triazole-Based 4-Thiazolidinones.

A series of 3-(2H-1,2,4-triazol-5-yl)-1,3-thiazolidin-4-one derivatives (7c–l) was designed and synthesized. Their structures have been elucidated based on analytical and spectral data. They were evaluated for their antibacterial and antifungal activities. Compound 7h showed the highest activity against all tested strains, except P. vulgaris, with MIC 8 μg/mL and 4 μg/mL against S. aureus and C. albicans, respectively. Furthermore, Compounds 7c, 7h, and 7j demonstrated moderate anti-mycobacterium activity. The binding mode of the synthesized thiazolidinones to bacterial MurB enzyme was also studied. Good interactions between the docked compounds to the MurB active site were observed primarily with Asn83, Arg310, Arg188 and Ser82 amino acid residues.