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, Год журнала: 2022, Номер 66(1), С. 777 - 792

Опубликована: Дек. 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.

Язык: Английский

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Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 1884 - 1902

Опубликована: Июль 8, 2022

A new series of 1H-pyrrole (6a-c, 8a-c), pyrrolo[3,2-d]pyrimidines (9a-c) and pyrrolo[3,2-e][1, 4]diazepines (11a-c) were designed synthesised. These compounds to have the essential pharmacophoric features EGFR Inhibitors, they shown anticancer activities against HCT116, MCF-7 Hep3B cancer cells with IC50 values ranging from 0.009 2.195 µM. value doxorubicin is 0.008 µM, 9a 9c showed 0.011 µM respectively HCT-116 cells. Compound 8b exerted broad-spectrum activity all tested cell lines an less than 0.05 was evaluated a panel kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 GSK3 alpha kinases 10-23% compared imatinib (1-10%). It has also arrested cycle at S phase. Its antiproliferative further augmented by molecular docking into active sites CDK2 cyclin A1.

Язык: Английский

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Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice

Life Sciences, Год журнала: 2023, Номер 316, С. 121390 - 121390

Опубликована: Янв. 14, 2023

Язык: Английский

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Novel imidazo[2,1-b]thiazoles and imidazo[1,2-a]pyridines tethered with indolinone motif as VEGFR-2 inhibitors and apoptotic inducers: Design, synthesis and biological evaluations

Bioorganic Chemistry, Год журнала: 2024, Номер 151, С. 107644 - 107644

Опубликована: Июль 15, 2024

Язык: Английский

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Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2

Life Sciences, Год журнала: 2022, Номер 309, С. 121048 - 121048

Опубликована: Окт. 7, 2022

Язык: Английский

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Biological evaluation, docking studies, and in silico ADME prediction of some pyrimidine and pyridine derivatives as potential EGFR ^WT and EGFR ^T790M inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 38(1), С. 176 - 191

Опубликована: Ноя. 1, 2022

Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx (HEP2), lung (H460), colon cancers (HCT116 Caco2), hypopharyngeal (FADU), normal Vero lines used. Compounds 8 14 displayed outstanding effects investigated further tested antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection DNA index using HEPG-2 line established both compounds as well. Furthermore, EGFR kinase (Wild T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, SAR studies carried out candidates.

Язык: Английский

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Design and Synthesis of 2-(4-Bromophenyl)Quinoline-4-Carbohydrazide Derivatives via Molecular Hybridization as Novel Microbial DNA-Gyrase Inhibitors

ACS Omega, Год журнала: 2023, Номер 8(20), С. 17948 - 17965

Опубликована: Май 11, 2023

Microbial DNA gyrase is regarded as an outstanding microbial target. Hence, 15 new quinoline derivatives (5-14) were designed and synthesized. The antimicrobial activity of the afforded compounds was pursued via in vitro approaches. investigated displayed eligible MIC values, particularly against G-positive Staphylococcus aureus species. Consequently, S. supercoiling assay performed, using ciprofloxacin a reference control. Obviously, 6b 10 unveiled IC50 values 33.64 8.45 μM, respectively. Alongside, exhibited value 3.80 μM. Furthermore, significant docking binding score encountered by compound (-7.73 kcal/mol), surpassing (-7.29 kcal/mol). Additionally, both revealed high GIT absorption without passing blood brain barrier. Finally, conducted structure-activity relationship study assured usefulness hydrazine moiety molecular hybrid for either cyclic or opened form.

Язык: Английский

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Design and synthesis of novel rigid dibenzo[ b,f ]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2023, Номер 38(1)

Опубликована: Янв. 11, 2023

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle following reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at NCI against a panel 60 cancer cell lines. Further, promising candidates (5a-g) for their ability to inhibit topoisomerase II, where 5e noticed be most active congener. Moreover, its cytotoxicity leukaemia SR cells. Also, arrested cycle G1 phase increased apoptosis ratio by 37.34%. Furthermore, in vivo studies showed inhibition tumour proliferation decrease volume. Histopathology liver enzymes examined as well. Besides, molecular docking, physicochemical, pharmacokinetic properties carried out. Finally, SAR study discussed open gate further optimisation candidate (5e).HighlightsTwo drug design.The lines.5e anti-topo II congener (IC50 = 6.36 ± 0.36 µM).5e cells cytotoxic effect confirmed 13.05 0.62 µM).In significantly inhibited 62.7% decreased volume 30.1 mm3 compared doxorubicin treatment.

Язык: Английский

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Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 67(1), С. 492 - 512

Опубликована: Дек. 20, 2023

Herein, modifications to the previously reported BIBR1591 were conducted obtain bioisosteric candidates with improved activities. The % inhibition of newly afforded against telomerase target was investigated. Notably, 6f achieved superior (63.14%) compared BIBR1532 and (69.64 51.58%, respectively). In addition, 8a 8b showed comparable promising 58.65 55.57%, respectively, which recorded be frontier that BIBR1591. 6f, 8a, tested five cancer cell lines related lung liver subtypes. Moreover, examined on both cycle progression apoptosis induction in HuH7 cells. Furthermore, vivo antitumor activity further assessed female mice solid Ehrlich carcinoma. molecular docking dynamics simulations carried out. Collectively, could considered potential new inhibitors subjected investigation and/or optimization.

Язык: Английский

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Novel asymmetrical azines appending 1,3,4-thiadiazole sulfonamide: synthesis, molecular structure analyses, in silico ADME, and cytotoxic effect

RSC Advances, Год журнала: 2023, Номер 13(15), С. 10353 - 10366

Опубликована: Янв. 1, 2023

Toward finding potential and novel anticancer agents, we designed prepared differently substituted unsymmetrical azine-modified thiadiazole sulfonamide derivatives using the "combi-targeting approach". An efficient procedure for synthesizing compounds starts with 5-acetyl-3-N-(4-sulfamoylphenyl)-2-imino-1,3,4-thiadi-azoline 4. The E/Z configuration compound 5 was investigated based on spectral analysis combined quantum mechanical calculation applying DFT-B3LYP method 6-31G(d) basis set. computational results found that E isomer energetically more favorable than Z by 2.21 kcal mol-1. Moreover, 1H 13C chemical shifts isomers in DMSO were predicted GIAO-B3LYP/6-31G(d) computations IEF-PCM solvation model. computed both are consistent those observed experimentally, indicating they exist solution phase. synthesized azines 7a-c, 9, 11, 13, 15a 15b also studied theoretically DFT-B3LYP/6-31G(d) calculations. In silico prediction biological activities reported regarding HOMO-LUMO energy gaps molecular reactivity descriptors besides ADMT/drug-likeness properties. cytotoxic effect of has been assayed via determination their IC50.

Язык: Английский

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