Pharmacognosy-to-Candidate: Protease-Directed Prioritization of Plant-Derived Glycosides via Minimal Semi-Synthetic Optimization

• Richa Singh

  Author

This study establishes an integrated pharmaceutical discovery pipeline from medicinal plant profiling to preclinical candidate identification, focusing on SARS-CoV-2 main protease (Mpro) inhibition. Comprehensive LC-ESI-TOF-MS/MS analysis of Cynanchum acutum L. identified 46 metabolites, with quercetin-3-O-β-galactoside (Q) characterized as the dominant flavonoid glycoside (3.71 mg/g crude extract) through validated HPTLC/HPLC methods. Strategic semi-synthetic optimization via selective O-alkylation generated two analogues (Q1: 7-benzyl; Q2: 7-bromoethyl) to enhance hydrophobicity and membrane permeability. Antiviral evaluation in Vero-E6 cells demonstrated significant SARS-CoV-2 inhibition, with the crude extract (IC₅₀ = 23.99 μg/mL, SI = 13.66) and benzyl derivative Q1 (IC₅₀ = 29.21 μg/mL, SI = 11.06) showing superior potency over the parent compound Q (IC₅₀ = 59.73 μg/mL, SI = 6.16). Molecular docking revealed preferential Mpro binding for Q1 (-8.34 kcal/mol) through conserved catalytic-site interactions with Cys145 and His41. The workflow exemplifies a minimal-chemistry approach from natural product hit to preclinical candidate, validated through orthogonal analytics and structure-activity relationships.

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