Targeting the interplay between MMP-2, CA II and VEGFR-2 via new sulfonamide-tethered isomeric triazole hybrids; Microwave-assisted synthesis, computational studies and evaluation

Aouad, Mohamed Reda; Almehmadi, Meshal A.; Albelwi, Fawzia Faleh; Teleb, Mohamed; Tageldin, Gina N.; Abu‐Serie, Marwa M.; Hagar, Mohamed; Rezki, Nadjet

doi:10.1016/j.bioorg.2022.105816

Cited by 19 publications

(10 citation statements)

References 126 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hybrid molecules that contain or are linked by a 1,2,3-triazole building block are usually referred to as “lead compounds”; these molecular hybrids offer a wide array of pharmacophore characteristics. Given the aforementioned features and researchers’ recent interest in the chemistry of 1,2,3-triazole molecules [ 13 , 46 , 47 , 48 ], novel 1,2,3-triazoles linked to pyrazole moiety for further investigation were designed and synthesized as lead compounds in medicinal chemistry as a continuation of our interest on these tunable scaffolds and their biological properties [ 49 , 50 , 51 , 52 , 53 ].…”

Section: Resultsmentioning

confidence: 99%

Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

et al. 2023

Self Cite

View full text Add to dashboard Cite

COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with prominent substituent functionalities were designed and synthesized via a click reaction based on our previous work. The novel compounds were assessed using an in vitro effect on the growth of SARS-CoV-2 virus-infested Vero cells with different compound concentrations: 1 and 10 μM. The data revealed that most of these derivatives showed potent cellular anti-COVID-19 activity and inhibited viral replication by more than 50% with no or weak cytotoxic effect on harboring cells. In addition, in vitro assay employing the SARS-CoV-2-Main protease inhibition assay was done to test the inhibitors’ ability to block the common primary protease of the SARS-CoV-2 virus as a mode of action. The obtained results show that the one non-linker analog 6h and two amide-based linkers 6i and 6q were the most active compounds with IC50 values of 5.08, 3.16, and 7.55 μM, respectively, against the viral protease in comparison to data of the selective antiviral agent GC-376. Molecular modeling studies were done for compound placement within the binding pocket of protease which reveal conserved residues hydrogen bonding and non-hydrogen interactions of 6i analog fragments: triazole scaffold, aryl part, and linker. Moreover, the stability of compounds and their interactions with the target pocket were also studied and analyzed by molecular dynamic simulations. The physicochemical and toxicity profiles were predicted, and the results show that compounds behave as an antiviral activity with low or no cellular or organ toxicity. All research results point to the potential usage of new chemotype potent derivatives as promising leads to be explored in vivo that might open the door to rational drug development of SARS-CoV-2 Main protease potent medicines.

show abstract

Section: Resultsmentioning

confidence: 99%

Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…The docking protocol was conducted as reported. 87–89 Sorafenib was docked into the active sites of VEGFR-2, where the ligand interactions were recreated with an acceptable binding energy (Δ G = −10.35 kcal mol −1 ) and RMSD values (1.39). As illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

Revealing the contributions of DFT to the spectral interpretation for an amino benzoyl thiourea derivative: Insights into experimental studies from theoretical perspectives, and biological evaluation

Hegazy,

Haiba,

Awad

et al. 2023

New J. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…HIA values > 70% (well absorbed), values ≈ 20%–70% (moderately absorbed), and values < 20% (poorly absorbed). [ 31 ]…”

Section: Resultsmentioning

confidence: 99%

“…PPB values > 90% (strongly bound), values < 90% (poorly bound). [31] j HIA: human intestinal absorption. HIA values > 70% (well absorbed), values ≈ 20%-70% (moderately absorbed), and values < 20% (poorly absorbed).…”

Section: In Silico Study Of Physicochemical Characteristics Admet Tox...mentioning

confidence: 99%

“…[30] Combining both pharmacophores, the triazole moiety and sulfathiazole in one scaffold afforded compounds 4 and 5, which were potent against HepG-2 with a considerable antiangiogenic effect. [27,31] On the other hand, different compounds that contain chalcone scaffolds exhibited potent anti-VEGFR-2 activity; a feature that makes it a very promising pharmacophore for the design of novel anticancer drugs. [32][33][34] Compound 6 showed high inhibitory effect against three cancer cell lines with anti-VEGFR-2 activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of novel sulfathiazole‐triazolo‐chalcone hybrids as VEGFR‐2/EGFR dual inhibitors with antiangiogenic activity and apoptotic induction

Zeidan,

Othman,

Goda

et al. 2023

Archiv der Pharmazie

View full text Add to dashboard Cite

Certain sulfathiazole‐triazolo chalcone hybrids were identified as anticancer agents with dual vascular endothelial growth factor receptor‐2 (VEGFR‐2)/epidermal growth factor receptor (EGFR) kinase inhibitory effect. All of the compounds were evaluated for their cytotoxic activity against the MCF‐7 and HepG‐2 tumor cell lines. Compounds 11g, 11h, and 11j exhibited the most potent antiproliferative activity against both cancer cell lines, with good safety toward WI‐38 normal cells. Thus, they were further assessed for VEGFR‐2 inhibitory activity. They have suppressed VEGFR‐2 enzyme at IC50 of 0.316, 0.076, and 0.189 µM, respectively in comparison to sorafenib (IC50 = 0.035 µM). EGFR enzyme inhibition was further screened for the most potent inhibitors, 11h and 11j, where they displayed enhanced potency with IC50 of 0.085 and 0.108 µM, respectively, compared to erlotinib (IC50 = 0.037 µM). Compounds 11h and 11j were additionally investigated for inhibition of comparable kinases, PDGFR‐β and B‐Raf, where results assessed adequate selectivity of both compounds toward the VEGFR‐2 and EGFR kinases. Furthermore, the wound healing assay of compound 11h manifested a percent wound closure of 65.18% in MCF‐7 cells compared to doxorubicin (58.51%) and untreated cells (97.77%), proving its antiangiogenic activity. The cell cycle assay of MCF‐7 cells treated with 11h demonstrated cell cycle arrest at the S phase. Moreover, compound 11h induced apoptosis with a 44‐fold increase compared to that induced in the control MCF‐7 cells. Molecular docking results of compounds 11h and 11j established their efficacies, and in silico studies showed convenient safety profiles with drug‐likeness properties.

show abstract

Targeting the interplay between MMP-2, CA II and VEGFR-2 via new sulfonamide-tethered isomeric triazole hybrids; Microwave-assisted synthesis, computational studies and evaluation

Cited by 19 publications

References 126 publications

Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

Revealing the contributions of DFT to the spectral interpretation for an amino benzoyl thiourea derivative: Insights into experimental studies from theoretical perspectives, and biological evaluation

Identification of novel sulfathiazole‐triazolo‐chalcone hybrids as VEGFR‐2/EGFR dual inhibitors with antiangiogenic activity and apoptotic induction

Contact Info

Product

Resources

About