Development of novel indolin-2-one derivative incorporating thiazole moiety as DHFR and quorum sensing inhibitors: Synthesis, antimicrobial, and antibiofilm activities with molecular modelling study

Ammar, Yousry A.; Abu-Elghait, Mohammed; Salem, Mohamed Salem Ould Ahmedou; Assiri, Mohammed A.; Ali, Tarik E.

doi:10.1016/j.bioorg.2021.105571

Cited by 56 publications

(68 citation statements)

References 75 publications

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“…The substituted 6-aminouracil derivatives 2a – e were obtained by adding urea, methyl urea, and/or methyl thiourea to ethyl cyanoacetate in absolute ethanol containing sodium (sodium ethoxide) by heating under reflux, according to the reported methods [ 21 , 22 ]. Additionally, 5-(substituted-sulfonyl)indoline-2,3-dione 1a – c were prepared according to the previously reported method [ 23 , 24 ].…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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 structure of the most active adamantane derivatives and positive controls (CIP and NV) were built using Gaussian View 5.0 software. 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 (Alzahrani, Ammar, Abu‐Elghait, et al, 2022; Alzahrani, Ammar, Salem, et al, 2022; Ammar et al, 2021; El‐Kalyoubi et al, 2022; all details and figures represented in Supporting Information).…”

Section: Methodsmentioning

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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“…Interestingly, we found that some compounds possess selectivity to target the QS systems (Table 1). Phenalinolactones A-D (35), BU-4664LMe (7), Dehydrogeldamycin (15), and Questinomycin A (50) significantly inhibited the agr QS systems without influencing the growth of S. aureus. Phenalinolactones A-D and BU-4664LMe exhibited a potent inhibitory activity (80%), while Dehydrogeldamycin and Questinomycin A showed moderate activity (50% inhibition).…”

Section: Screening Of Inhibitory Activity Of Actinomycetales Metaboli...mentioning

confidence: 99%

“…Further, Rakicidin A (45), Rakicidin B (9), and Lysolipin (28) exhibited a substantial influence on the growth of both S. aureus and E. faecalis without any significant effect on the agr/fsr QS systems. Excitingly, BU-4664LMe (7) and Synerazol (50) demonstrated the ability to inhibit both the agr and fsr QS systems. While BU-4664LMe exhibited a substantial inhibitory activity towards the fsr QS system (80%), it also showed the ability to inhibit the agr QS system with 30% at the tested concentration.…”

Section: Screening Of Inhibitory Activity Of Actinomycetales Metaboli...mentioning

confidence: 99%

“…The accessory gene regulator ( Agr ) is a well-characterized central regulatory locus of the QS system in the Gram-positive bacteria which has been extensively studied in S. aureus [ 4 , 5 ]. On the other hand, the fsr QS system, an ortholog of the agr-like QS system, has been found in E. faecalis [ 6 , 7 ]. While the agr QS system is mediated by thiolactone-autoinducing peptides, the fsr QS system is mediated by gelatinase biosynthesis-activating peptide (GBAP) containing lactone [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Development of novel indolin-2-one derivative incorporating thiazole moiety as DHFR and quorum sensing inhibitors: Synthesis, antimicrobial, and antibiofilm activities with molecular modelling study

Cited by 56 publications

References 75 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

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

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