Synthesis and mechanistic studies of diketo acids and their bioisosteres as potential antibacterial agents

Hasan, Phool; Pillalamarri, Vijaykumar; Aneja, Babita; Irfan, Mohammad; Azam, Mudsser; Perwez, Ahmad; Maguire, Ronan; Yadava, Umesh; Kavanagh, Kevin; Daniliuc, Constantin G.; Ahmad, Belal; Rizvi, M. Moshahid Alam; Haq, Qazi Mohd. Rizwanul; Addlagatta, A.; Abid, Mohammad

doi:10.1016/j.ejmech.2018.11.053

Cited by 8 publications

(6 citation statements)

References 35 publications

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“…Although more information is needed to prove MetAP as a selective drug target of compound 4l , our previous studies on heterocyclic compounds as inhibitors of MetAP and its crucial role in post-translational modifications of bacterial proteins prompt us to determine the binding pattern of 4l using an in silico approach. 34 Thus, docking studies were performed with MetAPs of E. coli (PDB ID: 1c21) and S. pneumoniae (PDB ID: 4km3) to support in vitro antibacterial results. Docking results of ligand 4l with Ec MetAP and Sp MetAP showed good interaction with binding energies of −7.6 and −7.0 kcal/mol, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…This process is highly crucial for the survival of bacterial cells, which enable MetAP as an emerging drug target for bacterial infections. Although more information is needed to prove MetAP as a selective drug target of compound 4l , our previous studies on heterocyclic compounds as inhibitors of MetAP and its crucial role in post-translational modifications of bacterial proteins prompt us to determine the binding pattern of 4l using an in silico approach . Thus, docking studies were performed with MetAPs of E.…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis, and Biological Evaluation of Novel Fused Spiro-4H-Pyran Derivatives as Bacterial Biofilm Disruptor

et al. 2019

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This study aims to synthesize novel fused spiro-4H-pyran derivatives under green conditions to develop agents having antimicrobial activity. The synthesized compounds were initially screened for in vitro antibacterial activity against two Gram-positive and three Gram-negative bacterial strains, and all the compounds exhibited moderate to potent antibacterial activity. However, compound 4l showed significant inhibition toward all the bacterial strains, particularly against Streptococcus pneumoniae and Escherichia coli with minimum inhibitory concentration values of 125 μg/mL for each. The toxicity studies of selected compounds (4c, 4e, 4l, and 4m) using human red blood cells as well as human embryonic kidney (HEK-293) cells showed nontoxic behavior at desired concentration. Growth kinetic and time–kill curve studies of 4l against S. pneumoniae and E. coli supported its bactericidal nature. Interestingly, compound 4l showed a synergistic effect when used in combination with ciprofloxacin against selected strains. Biofilm formation in the presence of a lead compound, as assessed by XTT assay, showed complete disruption of the bacterial biofilm visualized by scanning electron microscopy. Overall, the findings suggest 4l to be considered as a promising lead for further development as an antibacterial agent.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Fused Spiro-4H-Pyran Derivatives as Bacterial Biofilm Disruptor

et al. 2019

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“…The solution was stirred at room temperature for 1 h and then slowly poured into ice. To this cold mixture, 2 M HCl solution was added and the resulting suspension was filtered, and the collected solid was dried in air [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Mechanistic Studies of Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors

et al. 2022

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Methionine aminopeptidases (MetAPs) are attractive drug targets due to their essential role in eukaryotes as well as prokaryotic cells. In this study, biochemical assays were performed on newly synthesized Isatin-pyrazole hydrazones (PS1–14) to identify potent and selective bacterial MetAPs inhibitors. Compound PS9 inhibited prokaryotic MetAPs, i.e., MtMetAP1c, EfMetAP1a and SpMetAP1a with Ki values of 0.31, 6.93 and 0.37 µM, respectively. Interestingly, PS9 inhibited the human analogue HsMetAP1b with Ki (631.7 µM) about ten thousand-fold higher than the bacterial MetAPs. The in vitro screening against Gram-positive (Enterococcus faecalis, Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli) bacterial strains also exhibited their antibacterial potential supported by minimum bactericidal concentration (MBC), disk diffusion assay, growth curve and time-kill curve experiments. Additionally, PS6 and PS9 had synergistic effects when combined with ampicillin (AMP) and ciprofloxacin (CIP) against selective bacterial strains. PS9 showed no significant cytotoxic effect on human RBCs, HEK293 cells and Galleria mellonella larvae in vivo. PS9 inhibited the growth of multidrug-resistant environmental isolates as it showed the MIC lower than the standard drugs used against selective bacterial strains. Overall, the study suggested PS9 could be a useful candidate for the development of antibacterial alternatives.

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“…As described previously ( Hasan et al, 2019 ), a time-growth kinetics assay was performed for 21d against four Gram-positive bacteria. S. aureus , S. pneumonia , E. faecalis and S. xylosus of log-phase were inoculated in MH broth, which contained a range of compound 21d in different concentrations (1/4, 1/2, 1, 2 and 4 × MIC), and 1% DMSO was used as vehicle control and linezolid as a positive drug control in this assay.…”

Section: Time-growth Kinetics Assaymentioning

confidence: 99%

Synthesis and Biological Evaluation of 3-(Pyridine-3-yl)-2-Oxazolidinone Derivatives as Antibacterial Agents

et al. 2022

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In this research, a series of 3-(pyridine-3-yl)-2-oxazolidinone derivatives was designed, synthesized, and evaluated for in vitro antibacterial activity, which included bacteriostatic, morphological, kinetic studies, and molecular docking. The results demonstrated that compounds 21b, 21d, 21e and 21f exhibited strong antibacterial activity similar to that of linezolid toward five Gram-positive bacteria. After observing the effect of the drug on the morphology and growth dynamics of the bacteria, the possible modes of action were predicted by molecular docking. Furthermore, the antibiofilm activity and the potential drug resistance assay was proceeded. These compounds exhibited universal antibiofilm activity and compound 21d showed significant concentration-dependent inhibition of biofilm formation. Compound 21d also showed a stable effect on S. pneumoniae (ATCC 49619) with less drug resistance growth for 15 days, which is much longer than that of linezolid. Overall, these results can be used to guide further exploration of novel antimicrobial agents.

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Synthesis and mechanistic studies of diketo acids and their bioisosteres as potential antibacterial agents

Cited by 8 publications

References 35 publications

Design, Synthesis, and Biological Evaluation of Novel Fused Spiro-4H-Pyran Derivatives as Bacterial Biofilm Disruptor

Design, Synthesis, and Biological Evaluation of Novel Fused Spiro-4H-Pyran Derivatives as Bacterial Biofilm Disruptor

Design, Synthesis and Mechanistic Studies of Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors

Synthesis and Biological Evaluation of 3-(Pyridine-3-yl)-2-Oxazolidinone Derivatives as Antibacterial Agents

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