Scabies is a contagious parasitic skin infection caused by Sarcoptes scabiei mites, which is classified by WHO as a neglected tropical disease. The current study aims at shedding light on the scabicidal potential of some bioactive Amaryllidaceae alkaloids. All collected compounds were filtered based on ADME analysis, to yield 74 compounds for further in silico screening analysis. Network pharmacology predicted the anti-scabies and antipruritic potential of these alkaloids, via identification of key protein targets associated with scabies. This was achieved by analyzing data from bioinformatics databases. A Protein-Protein Interaction (PPI) network was constructed. Gene ontology analysis was performed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was also conducted. The investigations highlighted the genes crucial for immune response as CDC42BPA, PAK4, PAK6, PIK3CB, skin integrity as CTNND1), detoxification as EPHX1, GSTZ1 and cytoskeletal dynamics as IQGAP2, BAIAP2, and RTN). The docking results against the Glutathione S-transferase (GST) enzyme showed that most of the molecules attained moderate to strong docking scores with a special focus on cliviamartine and cripowellin B (S = −6.79 and −6.26 kcal/mol, respectively); compared to the co-crystallized ligand (S = −6.01 kcal/mol). The current work suggests that Amaryllidaceae alkaloids hold great potential as future candidates and offer novel therapeutic strategies for treating scabies.

Human scabies, a highly contagious parasitic skin infestation caused by Sarcoptes scabiei var. hominis mites, spreads rapidly through interpersonal contact. This study employed an integrated network pharmacology and molecular docking approach to identify shared therapeutic targets of seven structurally diverse Amaryllidaceae alkaloids (1–7) and evaluate their anti-scabies potential. A scabies-associated protein network was constructed, revealing interleukin-6 as the highest-degree node and a pivotal therapeutic target, alongside caspase-3. Sub sequent molecular docking analyses assessed the binding affinities and interaction stability of two promising alkaloids, narcissidine methyl ether (2) and crinine (3), with IL-6 and glutathione S-transferase (GST). Narcis sidine methyl ether demonstrated the strongest binding affinity to IL-6 (ΔG =–4.618 kcal/mol), while both compounds exhibited notable interactions with GST (ΔG =–5.917 and 4.885 kcal/mol, respectively). Computational screening confirmed their adherence to Lipinski’s and Veber’s rules, indicating favorable drug likeness properties. In vitro and in vivo experiments revealed significant acaricidal activity, with narcissidine methyl ether showing potent scabicidal effects. Histopathological evaluation of treated rabbit models demon strated marked improvement in ear auricle skin architecture three weeks post-treatment, supporting the thera peutic efficacy of both compounds. These findings highlight narcissidine methyl ether and crinine as promising anti-scabietic drugs, offering a foundation for future preclinical studies.