Anticancer Activity of Thiophene Carboxamide Derivatives as CA-4 Biomimetics: Synthesis, Biological Potency, 3D Spheroid Model, and Molecular Dynamics Simulation

Hawash, Mohammed; Qaoud, Mohammed T; Jaradat, Nidal; Abdallah, Samer; Issa, Shahd; Adnan, Nawal; Hoshya, Marah; Sobuh, Shorooq; Hawash, Zafer

doi:10.3390/biomimetics7040247

Cited by 19 publications

(19 citation statements)

References 58 publications

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“…The online WEBGRO Macromolecular Simulations server ( https://simlab.uams.edu/ProteinWithLigand/index.html ) was utilized to conduct molecular dynamics simulations based on GROMAC. It is a common public service that includes a GRACE High-Performance Computing Facility administrated by the University of Arkansas for Medical Sciences (UAMS) [ 51 , 52 ]. At first, the ligand topology was created utilizing the PRODRUG 2.3 online server ( http://davapc1.bioch.dundee.ac.uk/cgi-bin/prodrg/submit.html ) at GROMOS96 54a7 force field [ 53 ].…”

Section: Biological Methodsmentioning

confidence: 99%

Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents

Çapan,

Hawash,

Jaradat

et al. 2023

BMC Chemistry

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Background The carbazole skeleton is an important structural motif occurring naturally or synthesized chemically and has antihistaminic, antioxidant, antitumor, antimicrobial, and anti-inflammatory activities. Objectives This study aimed to design and synthesize a novel series of carbazole derivatives and evaluate their antiproliferative and antioxidant activities. Methods The synthesized compounds were characterized utilizing HRMS, 1H-, and 13CAPT-NMR, and assessed for their anticancer, antifibrotic, and antioxidant effects utilizing reference biomedical procedures. In addition, the AutoDock Vina application was used to perform in-silico docking computations. Results A series of carbazole derivatives were synthesized and characterized in the current study. Compounds 10 and 11 were found to have a stronger antiproliferative effect than compounds 2–5 against HepG2, HeLa, and MCF7 cancer cell lines with IC50 values of 7.68, 10.09, and 6.44 µM, respectively. Moreover, compound 9 showed potent antiproliferative activity against HeLa cancer cell lines with an IC50 value of 7.59 µM. However, except for compound 5, all of the synthesized compounds showed moderate antiproliferative activities against CaCo-2 with IC50 values in the range of 43.7–187.23 µM. All of these values were compared with the positive control anticancer drug 5-Fluorouracil (5-FU). In addition, compound 9 showed the most potent anti-fibrotic compound, and the cellular viability of LX-2 was found 57.96% at 1 µM concentration in comparison with the positive control 5-FU. Moreover, 4 and 9 compounds showed potent antioxidant activities with IC50 values of 1.05 ± 0.77 and 5.15 ± 1.01 µM, respectively. Conclusion Most of the synthesized carbazole derivatives showed promising antiproliferative, antioxidant, and antifibrotic biological effects, and further in-vivo investigations are needed to approve or disapprove these results.

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Section: Biological Methodsmentioning

confidence: 99%

Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents

Çapan,

Hawash,

Jaradat

et al. 2023

BMC Chemistry

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“…Finally, the model was built using the Swiss-Model web software ( , accessed on 10 September 2022) [ 95 ] and validated through the Ramachandran graph generated by the SAVES web software ( , accessed on 12 September 2022) [ 96 ]. Finally, the developed model was aligned with the original PDB (1aim) using the PyMol software, and the Root Mean Square deviation (RMSD) value was calculated for the final validation of the model [ 97 ].…”

Section: Methodsmentioning

confidence: 99%

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

et al. 2023

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The present study proposed the synthesis of a novel acridine derivative not yet described in the literature, chemical characterization by NMR, MS, and IR, followed by investigations of its antileishmanial potential. In vitro assays were performed to assess its antileishmanial activity against L. amazonensis strains and cytotoxicity against macrophages through MTT assay and annexin V-FITC/PI, and the ability to perform an immunomodulatory action using CBA. To investigate possible molecular targets, its interaction with DNA in vitro and in silico targets were evaluated. As results, the compound showed good antileishmanial activity, with IC50 of 6.57 (amastigotes) and 94.97 (promastigotes) µg mL−1, associated with non-cytotoxicity to macrophages (CC50 > 256.00 µg mL−1). When assessed by flow cytometry, 99.8% of macrophages remained viable. The compound induced an antileishmanial effect in infected macrophages and altered TNF-α, IL-10 and IL-6 expression, suggesting a slight immunomodulatory activity. DNA assay showed an interaction with the minor grooves due to the hyperchromic effect of 47.53% and Kb 1.17 × 106 M−1, and was sustained by docking studies. Molecular dynamics simulations and MM-PBSA calculations propose cysteine protease B as a possible target. Therefore, this study demonstrates that the new compound is a promising molecule and contributes as a model for future works.

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“…The CellTilter 96 aqueous one solution cell proliferation (MTS) test evaluated the viability of the cells (Promega Corporation, Madison, WI). 20 μL of MTS solution was added and incubated for 2 h, and then the absorbance was read by an ELISA reader at 49 nm and IC 50 was calculated …”

Section: Methodsmentioning

confidence: 99%

“…20 μL of MTS solution was added and incubated for 2 h, and then the absorbance was read by an ELISA reader at 49 nm and IC 50 was calculated. 38 Virtual Screening Analysis. Molecular Docking Studies.…”

Section: ■ Conclusionmentioning

confidence: 99%

New Thiazole Carboxamide Derivatives as COX Inhibitors: Design, Synthesis, Anticancer Screening, In Silico Molecular Docking, and ADME Profile Studies

Hawash,

Jaradat,

Sabobeh

et al. 2023

ACS Omega

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The goal of this work was to create and test a new series of thiazole carboxamide derivatives for their cyclooxygenase (COX) suppressor and anticancer effects. The compounds were characterized using 1H, 13C NMR, and HRMS spectrum analysis, and their selectivity toward COX-1 and COX-2 was assessed using an in vitro COX inhibition assay kit. Cytotoxicity was assessed using an MTS assay against a panel of cancer and normal cell lines. The docking studies were aided by the Prime MM-GBSA method for estimating binding affinities. The density functional theory (DFT) analysis was performed to assess compound chemical reactivity, which was calculated by computing the border orbital energy of both HOMO and LUMO orbitals, as well as the HOMO−LUMO energy gap. For ADME-T analysis, the QiKProp module was employed. Furthermore, using human X-ray crystal structures, molecular docking studies were carried out to discover the probable binding patterns of these drugs within both COX-1 and COX-2 isozymes. The results demonstrated that the most effective compound against the COX-1 enzyme was 2b with an IC 50 of 0.239 μM. It also showed potent activity against COX-2 with an IC 50 value of 0.191 μM and a selectivity ratio of 1.251. The highest selectivity ratio was 2.766 for compound 2a against COX-2 with an IC 50 dose of 0.958 μM relating to the celecoxib ratio of 23.8 and its IC 50 against COX-2 of 0.002 μM. Compound 2j also showed good selectivity toward COX-2 (1.507) with an IC 50 value of 0.957 μM. All compounds showed negligible cytotoxic activity against the evaluated normal cell lines, and the IC 50 values were more than 300 μM, except for compound 2b, whose IC 50 values were 203.71 ± 1.89 and 116.96 ± 2.05 μM against LX-2 and Hek293t cell lines, respectively. Moreover, compound 2b showed moderate anticancer activity against COLO205 and B16F1 cancer cell lines with IC 50 values of 30.79 and 74.15 μM, respectively.

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Anticancer Activity of Thiophene Carboxamide Derivatives as CA-4 Biomimetics: Synthesis, Biological Potency, 3D Spheroid Model, and Molecular Dynamics Simulation

Cited by 19 publications

References 58 publications

Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents

Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

New Thiazole Carboxamide Derivatives as COX Inhibitors: Design, Synthesis, Anticancer Screening, In Silico Molecular Docking, and ADME Profile Studies

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