Development of pyrazolo[1,5-a]pyrimidine-grafted coumarins as selective carbonic anhydrase inhibitors and tubulin polymerization inhibitors with potent anticancer activity

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 140462 - 140462

Published: Jan. 1, 2025

Language: Английский

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Novel N-(3-(1-(4-sulfamoylphenyl)triazol-4-yl)phenyl)benzamide Derivatives as Potent Carbonic Anhydrase Inhibitors with Broad-Spectrum Anticancer Activity: Leveraging Tail and Dual-Tail Approaches

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Carbonic anhydrases (CAs) IX and XII are crucial for the survival metastasis of solid tumors under hypoxic conditions. We designed compounds 7a–s, integrating triazole benzenesulfonamide scaffolds known inhibiting tumor-associated CAs IX/XII. Initial synthesis included 7a–e, followed by diversification with small hydrophobic groups (7f–m) hydrophilic heterocyclic secondary amines (7n–s). Compounds were evaluated against CA II, IX, to assess activity selectivity. Chlorinated derivative 7l exhibited highest efficacy (KI = 0.317 μM) ditrifluoromethylated 7j 0.081 μM). Subsequent testing on 60 cancer cell lines at 10 μM revealed promising anticancer activity, especially dimethylated 7h (CA KI 1.324 μM; XII, 0.435 μM), GI50 values ranging from 0.361 9.21 μM. Molecular docking analyses elucidated binding mechanisms, highlighting potential inhibitory actions compound XII.

Language: Английский

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Design, synthesis, and molecular dynamics-driven evaluation of quinoline-sulfonamide derivatives as potent and selective EGFR inhibitors with promising anti-cancer efficacy and safety profiles

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108247 - 108247

Published: Feb. 1, 2025

Language: Английский

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Novel Benzenesulfonamide Derivatives Linked to Diaryl Pyrazole Tail as Potential Carbonic Anhydrase II/VII Inhibitors with Anti-epileptic Activity

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117619 - 117619

Published: April 1, 2025

Language: Английский

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Shooting an Arrow against Convulsion: Novel Triazole-Grafted Benzenesulfonamide Derivatives as Carbonic Anhydrase II and VII Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

This study investigates new anticonvulsant substances that target the epilepsy-associated carbonic anhydrase isoforms II and VII. The 1,2,3-triazole with a benzenesulfonamide motif is present in produced molecules. Of these, 5b 5c exhibited remarkable selectivity inhibitory efficacy toward hCA VII over I. KI values of were 6.3 10.1 nM, respectively, 21.6 18.9 respectively. In pilocarpine-induced paradigm, vivo assessments showed decreased seizure severity susceptibility delayed onset diminished intensity. quick absorption stability demonstrated by pharmacokinetic investigations. Evaluations toxicity no neurotoxic effects high safety margin (LD50 > 2000 mg/kg). Mechanistic research has shown effectiveness maintaining neuronal integrity, reducing mTOR activation, raising hippocampus KCC2 levels. Compound 5b's binding interactions clarified docking dynamics experiments.

Language: Английский

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Molecular docking, DFT and antiproliferative properties of 4‐(3,4‐dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency

Drug Development Research, Journal Year: 2024, Volume and Issue: 85(7)

Published: Oct. 28, 2024

Abstract Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need develop novel therapeutic agents. 4‐(3,4‐Dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1 H ‐pyrazolo[3,4‐ b ]pyridine ( 3 ) was synthesized Initially screened on 59 cell lines showed promising anticancer activity, so, it chosen for 5‐dose experiment by NCI/USA. The GI 50 values ranged from 1.04 8.02 μM entire nine panels (57 lines), of 2.70 (MG‐MID) panel, indicating an encouraging action. To further explore molecular attributes compound , we optimized its structure using DFT B3LYP/6‐31 + G(d,p) basis set. We have considered vibrational analysis, bond lengths angles, FMOs, MEP structure. Additionally, pharmacokinetic assessments were conducted various in‐silico platforms evaluate safety. A modeling study created kinase profile 44 different kinases. This allowed us our compound's binding affinity these kinases compare co‐crystallized one. Our findings revealed exhibited better half tested kinases, suggesting potential as multi‐kinase inhibitor. validate computational results, inhibitory effects CDK2 PIM1. Compound IC 0.30 µM inhibition, making five times less active than Roscovitine, which has 0.06 µM. However, demonstrated slightly inhibition PIM1 compared Staurosporine. These suggest that agent development into highly compound.

Language: Английский

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New S- and N-alkyl functionalized bis-1,2,4-Triazolyl-based Derivatives as Potential Dual EGFRWT and EGFRT790M Inhibitors: Synthesis, Anti-proliferative Evaluation, Molecular Docking Study and ADMET Studies

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: unknown, P. 140720 - 140720

Published: Nov. 1, 2024

Language: Английский

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