Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action

Gouda, Ahmed M.; Beshr, Eman A. M.; Almalki, Faisal A.; Halawah, Hadeel H.; Taj, Batool Fawzi; Alnafaei, Athir Faiz; Alharazi, Rahaf Sulaiman; Kazi, Weam Mahmood; Almatrafi, Malak Mohammad

doi:10.1016/j.bioorg.2019.103224

Cited by 28 publications

(25 citation statements)

References 102 publications

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“…In the current study, the new compounds 16a – h exhibited potent antiproliferative activity against one or more of the three cancer cell lines at IC 50 values much lower than those of NSAIDs [ 2 , 38 ]. These results could be attributed to the ability of the new compounds to act on other targets besides the COX-2 enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…Before thirty years, the antiproliferative effect of nonsteroidal anti-inflammatory drugs (NSAIDs) was discovered [ 2 ]. Since then, there has been much greater interest from many researchers around the world, hoping to explore the antiproliferative potential of NSAIDs and investigate their mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Substantial research was also conducted to investigate the mechanism of action of NSAIDs [ 2 , 8 , 9 , 10 , 11 ]. Based on these studies, the anticancer activity of NSAIDs can be attributed to the COX-dependent mechanisms [ 2 ]. However, COX-independent mechanisms were also reported to mediate the anticancer potential of celecoxib 2 [ 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…To date, celecoxib is still the only NSAID that has been approved for FAP [ 6 ]. This may be attributed to the weak anticancer activities of NSAIDs or to their toxic side effects of these drugs [ 2 , 12 ]. According to this, extensive research in this field should be conducted to develop new scaffolds with potent anticancer activities and good safety profiles.…”

Section: Introductionmentioning

confidence: 99%

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In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

et al. 2021

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In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC50 = 0.01–40.50 μM) and one normal MRC5 (IC50 = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC50 = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G2/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

et al. 2021

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Exploring ibuprofen derivatives as α‐glucosidase and lipoxygenase inhibitors: Cytotoxicity and in silico studies

Daud

Abid

Sardar

et al. 2022

Archiv der Pharmazie

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This study reports the synthesis of a series of ibuprofen derivatives, including thiosemicarbazides 4a-f, 1,3,4-oxadiazoles 5a-f, 1,3,4-thiadiazoles 6a-f, 1,2,4triazoles 7a-f, and their S-alkylated derivatives 8a-d. All of the newly synthesized derivatives were analyzed using 1 H NMR, 13 C NMR spectroscopy, and highresolution mass spectra (electron ionization) spectrometry. These synthetic molecules were examined for their in vitro baking yeast α-glucosidase and soybean 15-lipoxygenase (15-LOX) inhibition and cell viability studies. The results revealed that the compounds N-(3,4-dichlorophenyl)−5-[1-(4-isobutylphenyl)ethyl]-1,3,4oxadiazol-2-amine 5f (IC 50 3.05 ± 1.23 µM) and N-(3-fluorophenyl)-5-[1-(4isobutylphenyl)ethyl]-1,3,4-oxadiazol-2-amine 5b (IC 50 3.12 ± 1.21 µM) were the most potent with respect to the α-glucosidase enzyme while in case of 15-LOX, the compound 4-(2,4-dichlorophenyl)-1-[2-(4-isobutylphenyl)propanoyl]thiosemicarbazide 4e showed potent inhibition with an IC 50 value of 55.41 ± 0.41 µM. All these compounds were found least toxic by displaying a blood mononuclear cell viability value of 69.2%-97.8% by the MTT assay compared to the standards when assayed at 0.25 mM concentration. Molecular docking analyses were conducted to evaluate the inhibition profiles of these derivatives against the said enzymes and the data supported the in vitro profiles.

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Molecular Docking, Synthesis, and Characterization of Furanyl‐Pyrazolyl Acetamide and 2,4‐Thiazolidinyl‐Furan‐3‐Carboxamide Derivatives as Neuroinflammatory Protective Agents

Mudimela,

Giridharan,

Janardhan

2024

Chemistry & Biodiversity

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Microglia are key immune cells in the brain that maintain homeostasis and defend against immune threats. Targeting the dysfunctional microglia is one of the most promising approaches to inhibit neuroinflammation. In the current study, a diverse series of molecular hybrids were designed and screened through molecular docking against two neuroinflammatory targets, namely HMGB1 (2LY4) and HMGB1 Box A (4QR9) proteins. Based on the outcomes of docking scores fifteen compounds; ten furanyl‐pyrazolyl acetamides 11(a‐j), and five 2,4‐thiazolidinyl‐furan‐3‐carboxamide 15(a‐e) derivatives were selected for further synthesis, followed by biological evaluation. The selected compounds, 11(a‐j) and 15(a‐e) were successfully synthesized with moderate to good yields, and structures were confirmed by IR, NMR, and mass spectra. The in‐vitro cytotoxicity was evaluated on microglial cells namely BV‐2, N‐9, HMO6, leukemic HAP1, and human fibroblast cells. Further western‐blot analysis revealed that 11h, 11f, 11c, 11j, 15d, 15c, 15e, and 15b compounds significantly suppressed anti‐inflammatory markers such as TNF‐α, IL‐1, IL‐6, and Bcl‐2. All derivatives were moderate in potency compared to reference doxorubicin and could potentially act as novel anti‐neuroinflammatory agents. This study can act as a beacon for further research in the application of furan‐pyrazole and furan‐2,4‐thiazolidinediones as lead moieties for anti‐neuroinflammatory and related diseases.

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Arylpropionic acid-derived NSAIDs: New insights on derivatization, anticancer activity and potential mechanism of action

Cited by 28 publications

References 102 publications

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

Exploring ibuprofen derivatives as α‐glucosidase and lipoxygenase inhibitors: Cytotoxicity and in silico studies

Molecular Docking, Synthesis, and Characterization of Furanyl‐Pyrazolyl Acetamide and 2,4‐Thiazolidinyl‐Furan‐3‐Carboxamide Derivatives as Neuroinflammatory Protective Agents

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