Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA

Ibrahim, Seham A.; Fayed, Eman A.; Rizk, Hala F.; Desouky, Said E.

doi:10.1016/j.bioorg.2021.105339

Cited by 48 publications

(27 citation statements)

References 71 publications

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“…The structure of AgrA was prepared for molecular docking using the Protonate 3D protocol in MOE with the default options. The Triangle Matcher placement method and London dG scoring function were applied in the docking protocol according to the reported procedure [ 58 , 59 , 60 , 64 , 65 , 66 , 67 ].…”

Section: Methodsmentioning

confidence: 99%

Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study

et al. 2022

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Anti-virulence agents are non-bacteriostatic and non-bactericidal emerging therapeutic options which hamper the production of virulence factors in pathogenic flora. In Staphylococcus aureus and Enterococcus faecalis, regulation of virulence genes’ expression occurs through the cyclic peptide-mediated accessory gene regulator (agr) and its ortholog fsr quorum sensing systems, respectively. In the present study, we screened a set of 54 actinomycetales secondary metabolites as novel anti-virulence compounds targeting quorum sensing system of the Gram-positive bacteria. The results indicated that four compounds, Phenalinolactones A–D, BU–4664LMe, 4,5-dehydrogeldamycin, and Questinomycin A, potentially inhibit the agr quorum sensing system and hemolytic activity of S. aureus. On the other hand, Decatromicin A and B, Okilactomycin, Rishirilide A, Abyssomicin I, and Rebeccamycin selectively blocked the fsr quorum sensing system and the gelatinase production in E. faecalis at sub-lethal concentrations. Interestingly, Synerazol uniquely showed the capability to inhibit both fsr and agr quorum sensing systems. Further, in silico molecular docking studies were performed which provided closer insights into the mode of action of these compounds and proposed that the inhibitory activity of these compounds could be attributed to their potential ability to bind to the ATP-active site of S. aureus AgrA. Taken together, our study highlights the potential of actinomycetales secondary metabolites with diverse structures as anti-virulence quorum sensing inhibitors.

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Section: Methodsmentioning

confidence: 99%

Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study

et al. 2022

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“…Pre-molecular docking simulations were completed using Molecular Operating Environmental (MOE) software version 2008.10 (Hassan et al, 2021 ; Ibrahim et al, 2021a , 2021b ). The docking processes for all drugs were performed according to the reported method (Fukuda et al, 2017 ) using the Triangle Matcher placement method and London dG as a scoring function.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic strategies for Covid-19 based on molecular docking and dynamic studies to the ACE-2 receptors, Furin, and viral spike proteins

Khattab

Abol-Ftouh

Elhenawy

2021

Journal of Biomolecular Structure and Dynamics

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SARS-CoV-2 is a pandemic virus that caused infections and deaths in many world countries, including the Middle East. The virus-infected human cells by binding via ACE-2 receptor through the Spike protein of the virus with Furin's help causing cell membrane fusion leading to Covid-19-cell entry. No registered drugs or vaccines are triggering this pandemic viral disease yet. Our present work is based on molecular docking and dynamics simulation that performed to spike protein-ACE-2 interface complex, ACE-2 receptor, Spike protein (RBD), and Furin as targets for new small molecules. These drugs target new potential therapies to show their probabilities toward the active sites of mentioned proteins, strongly causing inhibition and/or potential therapy for covid-19. All target proteins were estimated against new target compounds under clinical trials and repurposing drugs currently present. Possibilities of those molecules and potential therapeutics acting on a certain target were predicted. MD simulations over 200 ns with molecular mechanics-generalized Born surface area (MMGBSA) binding energy calculations were performed. The structural and energetic analyses demonstrated the stability of the ligands-M Pros complex. Our present work will introduce new visions of some biologically active molecules for further studies in-vitro and in-vivo for Covid-19, repurposing of these molecules should be taking place under clinical works and offering different strategies for drugs repurposing against Covid-19 diseases. Communicated by Ramaswamy H. Sarma.

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“…It was hypothesized that the hybridization of two or more pharmacologically active components in the molecular architecture of hybrid compound/conjugate would prove to be a promising chemotherapeutic agent [ 15 , 16 , 17 , 18 ]. As a result of these findings, and as part of our medicinal program aimed at the discovery of novel biologically important heterocyclic compounds with various biological activities [ 19 , 20 ], we integrated the structural features of isatin to design and synthesize a new class of isatin–pyridine-pyrimidine conjugates, hoping to identify novel functional molecules with potent antiviral effects. The results may provide useful information for the design of novel chemotherapeutic drugs ( Figure 3 ).…”

Section: Introductionmentioning

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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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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Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA

Cited by 48 publications

References 71 publications

Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study

Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study

Therapeutic strategies for Covid-19 based on molecular docking and dynamic studies to the ACE-2 receptors, Furin, and viral spike proteins

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

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