Future medicinal chemistry · 2026
Targeting traumatic brain injury via novel tetrahydrocarbazole derivatives: in silico design, synthesis, and in vitro evaluation of dual NADPH oxidase 2 and 4 inhibitors.
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: The upregulation of NADPH oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) contributes to traumatic brain injury (TBI)-induced oxidative stress and neurodegeneration. This study designed, synthesized, and evaluated 19 sulfonamide-substituted tetrahydrocarbazole derivatives as dual NOX2/NOX4 inhibitors.
MATERIALS AND METHODS: In silico studies used molecular docking and 100-ns molecular dynamics simulations with NOX2 crystal structure (PDB ID: 8WEJ) and AlphaFold-predicted NOX4 model (UniProt Q9NPH5). Compounds were synthesized via Borsche-Drechsel cyclization and evaluated in HL-60 cells using ELISA kits quantifying NOX, NOX2, and NOX4 protein levels.
RESULTS: Docking identified N,9-diethyl-N-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamide (B1) as lead (NOX2: -6.46 kcal/mol; NOX4: -5.66 kcal/mol), with π-cation (Arg513), hydrogen bonding (Arg446), and π-anion (Asp474) interactions. MD confirmed stability (RMSD ~0.2-0.3 nm, RMSF <0.20 nm). B1 showed balanced inhibition: total NOX IC50 04.30 ± 0.26 ng/mL, NOX2 02.80 ± 0.04 ng/mL, NOX4 137.18 ± 3.67 pg/mL (comparable to GSK2795039 01.10 nM NOX2 and GLX351322 125.79 pg/mL NOX4).
CONCLUSIONS: B1 demonstrates potent, isoform-selective dual NOX2/NOX4 inhibition with drug-like properties (MW 320.45 Da, LogP 3.01, BBB-permeable), offering a promising scaffold for TBI neuroprotection.
MATERIALS AND METHODS: In silico studies used molecular docking and 100-ns molecular dynamics simulations with NOX2 crystal structure (PDB ID: 8WEJ) and AlphaFold-predicted NOX4 model (UniProt Q9NPH5). Compounds were synthesized via Borsche-Drechsel cyclization and evaluated in HL-60 cells using ELISA kits quantifying NOX, NOX2, and NOX4 protein levels.
RESULTS: Docking identified N,9-diethyl-N-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamide (B1) as lead (NOX2: -6.46 kcal/mol; NOX4: -5.66 kcal/mol), with π-cation (Arg513), hydrogen bonding (Arg446), and π-anion (Asp474) interactions. MD confirmed stability (RMSD ~0.2-0.3 nm, RMSF <0.20 nm). B1 showed balanced inhibition: total NOX IC50 04.30 ± 0.26 ng/mL, NOX2 02.80 ± 0.04 ng/mL, NOX4 137.18 ± 3.67 pg/mL (comparable to GSK2795039 01.10 nM NOX2 and GLX351322 125.79 pg/mL NOX4).
CONCLUSIONS: B1 demonstrates potent, isoform-selective dual NOX2/NOX4 inhibition with drug-like properties (MW 320.45 Da, LogP 3.01, BBB-permeable), offering a promising scaffold for TBI neuroprotection.