Future medicinal chemistry · 2026
Novel derivatives of tetrahydrocarbazole as NADPH oxidase 2 and 4 inhibitors: in silico, synthesis, and in vitro evaluation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Pathania Akashdeep Singh, Badhai Kavita, Singh Nirmal, Chopra Dimple Sethi, Singh Dhandeep
Аннотация
AIM: Post-traumatic oxidative stress mediated by NADPH oxidase (NOX) isoforms NOX2 and NOX4 is a critical pathogenic mechanism in traumatic brain injury (TBI), yet no direct pharmacological inhibitors are available. This study aimed to design, synthesize, and evaluate N-substituted tetrahydrocarbazole-6-sulfonamide derivatives as inhibitors of NOX2 and NOX4.
MATERIALS AND METHODS: Twenty derivatives were rationally designed using carbazole scaffold with varied N-alkyl and N-aryl substituents to optimize lipophilicity and membrane permeability. Virtual screening against NOX2 (PDB: 8WEJ) and AlphaFold-predicted NOX4 structure identified lead compounds ASP5, ASP11, and ASP18 with docking scores of -7.84 to -8.76 kcal/mol. Molecular dynamics simulations (100 ns) confirmed stable binding (RMSD < 2.0 Å). Compounds were synthesized via Borsche - Drechsel cyclization and sulfonamide coupling and characterized by NMR and LC-MS. ELISA determined IC50 values for total NOX, NOX2, and NOX4 inhibition in HL-60 cells.
RESULTS: ASP1 showed the highest total NOX inhibition (IC50 4.69 ± 0.23 ng/mL), ASP5 was most selective for NOX2 (2.68 ± 0.10 ng/mL), and ASP20 exhibited highest NOX4 potency (127.77 ± 9.11 pg/mL). N-alkyl substituents favored NOX2 inhibition, whereas N-aryl groups enhanced NOX4 selectivity.
CONCLUSIONS: Tetrahydrocarbazole-6-sulfonamides represent a versatile scaffold for selective inhibition of NOX2 and NOX4, with ASP5 and ASP20 identified as promising leads for targeting NOX-mediated oxidative stress in TBI.
MATERIALS AND METHODS: Twenty derivatives were rationally designed using carbazole scaffold with varied N-alkyl and N-aryl substituents to optimize lipophilicity and membrane permeability. Virtual screening against NOX2 (PDB: 8WEJ) and AlphaFold-predicted NOX4 structure identified lead compounds ASP5, ASP11, and ASP18 with docking scores of -7.84 to -8.76 kcal/mol. Molecular dynamics simulations (100 ns) confirmed stable binding (RMSD < 2.0 Å). Compounds were synthesized via Borsche - Drechsel cyclization and sulfonamide coupling and characterized by NMR and LC-MS. ELISA determined IC50 values for total NOX, NOX2, and NOX4 inhibition in HL-60 cells.
RESULTS: ASP1 showed the highest total NOX inhibition (IC50 4.69 ± 0.23 ng/mL), ASP5 was most selective for NOX2 (2.68 ± 0.10 ng/mL), and ASP20 exhibited highest NOX4 potency (127.77 ± 9.11 pg/mL). N-alkyl substituents favored NOX2 inhibition, whereas N-aryl groups enhanced NOX4 selectivity.
CONCLUSIONS: Tetrahydrocarbazole-6-sulfonamides represent a versatile scaffold for selective inhibition of NOX2 and NOX4, with ASP5 and ASP20 identified as promising leads for targeting NOX-mediated oxidative stress in TBI.