One-pot strategy for thiazole tethered 7-ethoxy quinoline hybrids: Synthesis and potential antimicrobial agents as dihydrofolate reductase (DHFR) inhibitors with molecular docking study

Ammar, Yousry A.; El-Hafez, Sondos M.A. Abd; Hessein, Sadia A.; Ali, Abeer M.; Askar, Ahmed; Ragab, Ahmed

doi:10.1016/j.molstruc.2021.130748

Cited by 39 publications

(38 citation statements)

References 67 publications

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“…The molecular modelling calculation using the DFT method was carried out to evaluate and specify the relationship between the structure of the most active derivatives and the experimental activity results. Additionally, the geometrical optimization of the most promising derivatives 3a , 4b , 4d , 4e and positive controls ( Chloroquine and Remdesivir ) were calculated by the DFT method that was used to determine the frontier energies of molecular orbital, and therefore deduce some quantum molecular parameters according to previously reported methods [ 32 , 33 ], as described in Table 5 and Table 6 .…”

Section: Resultsmentioning

confidence: 99%

“…The geometrical optimization of the most active derivatives 3a , 4b , 4d , 4e and positive controls ( Chloroquine and Remdesivir) were performed using DFT methods through the Gaussian 09 set of the program according to previously reported methods [ 32 ]. The global descriptors of chemical reactivity are related to frontier molecular orbital and are calculated simply depending on previously reported methods [ 44 , 45 ].…”

Section: Methodsmentioning

confidence: 99%

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One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein

El‐Kalyoubi

Ali

Seadawy³

et al. 2022

Pharmaceuticals

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The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives 2a–e and isatin derivatives 1a-c to synthesize spiro-oxindoles 3a–d, 4a–e, and 5a–e. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5’-pyrido[2 ,3-d:6,5-d’]dipyrimidine derivatives 3a, 4b, 4d, and 4e showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein

El‐Kalyoubi

Ali

Seadawy³

et al. 2022

Pharmaceuticals

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“…Gaussian 09 software was used to calculate DFT and molecular electrostatic potential (MEP) after optimizing the synthesized derivative using the B3LYP hybrid functional and standard 6-31G(d) basis set as described previously Ammar et al, 2021;El-Kalyoubi et al, 2022; all details and figures represented in Supporting Information).…”

Section: Geometry Optimization Study (Frontier Molecular Orbitals)mentioning

confidence: 99%

A new exploration toward adamantane derivatives as potential anti‐MDR agents: Design, synthesis, antimicrobial, and radiosterilization activity as potential topoisomerase IV and DNA gyrase inhibitors

Abusaif

Aboul-Magd

Wassel

et al. 2022

Drug Development Research

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Developing novel antimicrobial agents has become a necessitate due to the increasing rate of microbial resistance to antibiotics. All the newly adamantane derivatives were evaluated for their antimicrobial activities against six MDR clinical pathogenic isolates. The results exhibited that 13 compounds have from potent to good activity. Among those, five derivatives (6, 7, 9, 14a, and 14b) displayed the potent activities against the different isolates tested (MIC < 0.25 µg/ml with bacteria and <8 µg/ml with fungi) compared with Ciprofloxacin (CIP) and Fluconazole (FCA). Additionally, the potent adamantanes showed bactericidal and fungicidal effects based on (MBCs and MFCs) and the time‐kill assay. The most active adamantane derivatives 7 and 14b exhibited a synergistic effect of ΣFIC ≤ 0.5 with CIP and FCA against the bacterial and fungal isolates. Moreover, no antagonistic effect appeared for the tested derivatives. Additionally, the interaction of DNA gyrase and topoisomerase IV enzymes with the compounds 6, 7, 9, 14a, and 14b exhibited potent antimicrobial activity using in vitro biochemical assays and gel‐based DNA‐supercoiling inhibition method. The activity of DNA gyrase and topoisomerase IV enzymes showed inhibitory activity (IC50) of 6.20 µM and 9.40 µM with compound 7 and 10.14 µM and 13.28 µM with compound 14b, respectively. Surprisingly, exposing compound 7 to gamma irradiation sterilized and increased its activity. Finally, the in‐silico analysis predicted that the most active derivatives had good drug‐likeness and safe properties. Besides, molecular docking and quantum chemical studies revealed several important interactions inside the active sites and showed the structural features necessary for activity.

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“…Simultaneously, the DFT calculation and MEP were obtained through Gaussian 09 software after optimizing the synthesized derivatives with DFT calculations using the B3LYP hybrid functional and standard 6-31G(d) basis set according to the reported method. [82,83,97] (all details and figures are represented in the Supporting Information file. )…”

Section: Computational Studymentioning

confidence: 99%

Design, synthesis, molecular modeling, and antimicrobial potential of novel 3‐[(1H‐pyrazol‐3‐yl)imino]indolin‐2‐one derivatives as DNA gyrase inhibitors

Ammar

Salem

Abu-Elghait

2021

Archiv der Pharmazie

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A series of 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives were designed using the molecular hybridization method, characterized using different spectroscopic techniques, and evaluated for their in vitro antimicrobial activity. Most of the target compounds demonstrated good to moderate antimicrobial activity compared with ciprofloxacin and fluconazole. Four compounds (8b, 9a, 9c, and 10a) showed encouraging results, with minimal inhibitory concentration (MIC) values (53.45-258.32 µM) comparable to those of norfloxacin (100.31-200.63 µM) and ciprofloxacin (48.33-96.68 µM). Noticeably, the four derivatives revealed excellent bactericidal and fungicidal activities, except for the bacteriostatic potential of compounds 8b and 9a against Escherichia coli and Staphylococcus aureus, respectively. The time-killing kinetic study against S. aureus confirmed the efficacy of these derivatives. Furthermore, two of the four promising derivatives, 9a and 10a, could prevent the formation of biofilms of S. aureus without affecting the bacterial growth at low concentrations. A combination study with seven commercial antibiotics against the multidrug-resistant bacterium P. aeruginosa showed a notable reduction in the antibiotic MIC values, represented mainly through a synergistic or additive effect. The enzymatic assay implied that the most active derivatives had inhibition potency against DNA gyrase comparable to that of ciprofloxacin. Molecular docking and density functional theory calculations were performed to explore the binding mode and study the reactivity of the promising compounds.3-(pyrazol-3-yl)imino-2-oxoindoline derivatives, antibiofilm, antimicrobial activity, DFT calculations, DNA gyrase, drug combination, molecular docking, time-killing kinetics | INTRODUCTIONIn recent years, infectious diseases caused by bacterial pathogens have become a main public health problem due to the high occurrence of drug resistance. [1] Additionally, infections caused by multidrug-resistant bacteria are a major health concern worldwide. [2] Particularly important are infections caused by the Gram-positive bacteria Staphylococcus aureus and species of the genus Enterococcus due to the increasing incidence of infections caused by these microorganisms in hospitals and communities and their ability to

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One-pot strategy for thiazole tethered 7-ethoxy quinoline hybrids: Synthesis and potential antimicrobial agents as dihydrofolate reductase (DHFR) inhibitors with molecular docking study

Cited by 39 publications

References 67 publications

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein

A new exploration toward adamantane derivatives as potential anti‐MDR agents: Design, synthesis, antimicrobial, and radiosterilization activity as potential topoisomerase IV and DNA gyrase inhibitors

Design, synthesis, molecular modeling, and antimicrobial potential of novel 3‐[(1H‐pyrazol‐3‐yl)imino]indolin‐2‐one derivatives as DNA gyrase inhibitors

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