Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 777 - 792

Published: Dec. 16, 2022

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising inhibitors. Therefore, two novel series of pyridazine-linked cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized investigate the inhibitory activity candidates. Notably, 8e 9e exhibited best inhibition profiles. Moreover, showed strong antitumor effects against both MCF-7 A549 cell lines. The on cycle apoptosis measured. Besides, evaluated its in vivo using solid Ehrlich carcinoma. reduction tumor weight volume greater than doxorubicin. Also, molecular docking ADME studies performed. Finally, SAR study conducted gain further insights into different potentials upon variable structural modifications.

Language: Английский

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Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, andin silicostudies

RSC Advances, Journal Year: 2023, Volume and Issue: 13(18), P. 12184 - 12203

Published: Jan. 1, 2023

In this article, we continued our previous effort to develop new selective anticancer candidates based on the basic pharmacophoric requirements of both EGFR and VEGFR-2 inhibitors. Therefore, twenty-two novel 4-thiophenyl-pyrazole, pyridine, pyrimidine derivatives were designed examined as dual EGFR/VEGFR-2 Besides, previously reported antimicrobial activities aforementioned nuclei motivated us screen their antibacterial antifungal well. First, antitumor newly synthesized evaluated against two cancer cell lines (HepG-2 MCF-7). Notably, compounds 2a, 6a, 7a, 10b, 15a, 18a exhibited superior HepG-2 MCF-7 lines. These selected further evaluate anti-EGFR anti-VEGFR-2 potentialities which found be very promising compared erlotinib sorafenib, respectively. Both 10b 2a achieved better inhibition with IC50 values 0.161 0.141 μM 0.209 0.195 μM, Moreover, most active was exact phase cycle arrest investigate mechanism death whether it due apoptosis or necrosis. On other hand, all tested Gram-positive bacteria such S. aureus B. subtilis well Gram-negative E. coli P. aeuroginosa. Also, activity investigated C. albicans A. flavus strains. The findings tests revealed that strong moderate effects. Furthermore, understand pattern by bound site, subjected different docking processes into binding sites. tried correlate compound reference drugs (erlotinib sorafenib) through DFT calculations. Finally, following biological data pyrazole, candidates, concluded a interesting SAR for optimization.

Language: Английский

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Novel fused imidazotriazines acting as promising top. II inhibitors and apoptotic inducers with greater selectivity against head and neck tumors: Design, synthesis, and biological assessments

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 259, P. 115661 - 115661

Published: July 18, 2023

Language: Английский

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Synthesis of novel bioactive pyrido[2,3-d]pyrimidine derivatives with potent cytotoxicity through apoptosis as PIM-1 kinase inhibitors

RSC Advances, Journal Year: 2024, Volume and Issue: 14(16), P. 11098 - 11111

Published: Jan. 1, 2024

Novel bioactive pyrido[2,3- d ]pyrimidine derivatives with potent apoptotic inducers as PIM-1 kinase inhibitors.

Language: Английский

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Design and synthesis of novel chloropyridazine hybrids as promising anticancer agents acting by apoptosis induction and PARP-1 inhibition through a molecular hybridization strategy

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(3), P. 981 - 997

Published: Jan. 1, 2024

Novel chloropyridazine hybrids as promising anticancer agents acting by apoptosis induction and PARP-1 inhibition through a molecular hybridization strategy.

Language: Английский

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An overview of compound properties, multiparameter optimization, and computational drug design methods for PARP-1 inhibitor drugs

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 252, P. 115300 - 115300

Published: March 22, 2023

Language: Английский

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Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(5)

Published: Jan. 31, 2024

Abstract Two new series of quinazoline‐chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5‐trimethoxyphenyl chalcone moiety, showed effective inhibition value panel lines. Thus, it was selected for further investigation 5 log doses. Interestingly, this trimethoxy‐substituted analog inhibited proliferation Roswell Park Memorial Institute (RPMI)‐8226 cells by 96%, at 10 µM with IC 50 = 9.09 ± 0.34 selectivity index 7.19 normal blood cells. To confirm compound, evaluated tyrosine kinase enzymes. Mechanistically, successfully selectively HDAC6, HDAC8, EGFR 0.41 0.015, 0.61 0.027, 0.09 0.004 µM, respectively. Furthermore, derivative induced apoptosis via mitochondrial apoptotic pathway raising Bax/Bcl‐2 ratio activating caspases 3, 7, 9. Also, flow cytometry analysis RPMI‐8226 that produced cycle arrest G1 S phases 55.82%. Finally, an silico study performed to explore binding interaction active within zinc‐containing site HDAC6 HDAC8.

Language: Английский

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Synthesis and Biological Studies of Acetophenone-Based Novel Chalcone, Semicarbazone, Thiosemicarbazone and Indolone Derivatives: Structure-Activity Relationship, Molecular Docking, Molecular Dynamics, and Kinetic Studies

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1321, P. 140197 - 140197

Published: Sept. 26, 2024

Language: Английский

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Design and Synthesis of New Quinazolinone Derivatives Conjugated with Chalcone or Pyridazine Moieties: Anticancer Activities and Apoptotic Induction

Polycyclic aromatic compounds, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 24

Published: March 3, 2025

Language: Английский

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Current scenario of chalcone hybrids with antibreast cancer therapeutic applications

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(5)

Published: Jan. 16, 2024

Abstract Breast cancer, an epithelial malignant tumor that occurs in the terminal ducts of breast, is most common female malignancy. Currently, approximately 70%–80% breast cancer with early‐stage, nonmetastatic disorder curable, but emergency drug resistance often leads to treatment failure. Moreover, advanced distant organ metastases incurable available therapeutics, creating urgent demand explore novel antibreast agents. Chalcones, precursors for flavonoids and isoflavonoids, exhibit promising activity against various hallmarks, inclusive proliferation, angiogenesis, invasion, metastasis, inflammation, stemness, regulation epigenetics, representing useful scaffolds discovery chemotherapeutic candidates. In particular, chalcone hybrids could act on two or more different biological targets simultaneously efficacy, lower toxicity, less susceptibility resistance. Accordingly, there a huge scope application tackle present difficulties therapy. This review outlines potential developed from 2018. The structure–activity relationships as well mechanisms action are also discussed shed light development effective multitargeted

Language: Английский

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