N-Desethyl amodiaquine is an antiparasitic agent, has inhibitory for strains V1/S and 3D7 with IC50 values of 97nM and 25nM, respectively[1]. N-Desethyl amodiaquine is the major metabolite of the antimalarial compound aminodiaquine, produced by the action of cytochrome P450 isoform 2C8[2]. N-Desethyl amodiaquine is highly active against Plasmodium falciparum and can synergize with amodiaquine, usually used in the research of malaria[3-4].
In vitro, treatment with N-Desethyl amodiaquine significantly blocked viral replication in both Huh 7 and Vero E6 cell lines infected with Ebola virus, with IC50 values of 2.8μM and 11μM[5]. Treatment of RAW264.7 cells with N-Desethyl amodiaquine (8, 16, 33, or 66μM) for 1h before 6h intoxication with 500ng/mL protective antigen (PA)+ 500ng/mL lethal factor (LF) inhibited proteinase B activity in a dose-dependent manner and reduced toxin-mediated cytotoxicity[6].
In vivo, intravenous injection of N-Desethyl amodiaquine (3, 6mg/kg) inhibits PA-LF induced death in the Sprague−Dawley rat model by inhibiting cytosolic entry of LF[6]. Oral administration of N-Desethyl amodiaquine every 12h for 5 days at 5, 10, and 50mg/kg protects mice challenged with B. Anthracis Spores while decreasing survival times at increased N-Desethyl amodiaquine doses[7].
References:
[1] Sasi, P., Abdulrahaman, A., Mwai, L., Muriithi, S., Straimer, J., Schieck, E., Rippert, A., Bashraheil, M., Salim, A., Peshu, J., Awuondo, K., Lowe, B., Pirmohamed, M., Winstanley, P., Ward, S., Nzila, A., & Borrmann, S. (2009). In vivo and in vitro efficacy of amodiaquine against Plasmodium falciparum in an area of continued use of 4-aminoquinolines in East Africa. The Journal of infectious diseases, 199(11), 1575–1582.
[2] Li, X. Q., Björkman, A., Andersson, T. B., Ridderström, M., & Masimirembwa, C. M. (2002). Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. The Journal of pharmacology and experimental therapeutics, 300(2), 399–407.
[3] Mariga, S. T., Gil, J. P., Sisowath, C., Wernsdorfer, W. H., & Björkman, A. (2004). Synergism between amodiaquine and its major metabolite, desethylamodiaquine, against Plasmodium falciparum in vitro. Antimicrobial agents and chemotherapy, 48(11), 4089–4096.
[4] Childs, G. E., Boudreau, E. F., Milhous, W. K., Wimonwattratee, T., Pooyindee, N., Pang, L., & Davidson, D. E., Jr (1989). A comparison of the in vitro activities of amodiaquine and desethylamodiaquine against isolates of Plasmodium falciparum. The American journal of tropical medicine and hygiene, 40(1), 7–11.
[5] DeWald, L. E., Johnson, J. C., Gerhardt, D. M., Torzewski, L. M., Postnikova, E., Honko, A. N., Janosko, K., Huzella, L., Dowling, W. E., Eakin, A. E., Osborn, B. L., Gahagen, J., Tang, L., Green, C. E., Mirsalis, J. C., Holbrook, M. R., Jahrling, P. B., Dyall, J., & Hensley, L. E. (2019). In Vivo Activity of Amodiaquine against Ebola Virus Infection. Scientific reports, 9(1), 20199.
[6] Zilbermintz, L., Leonardi, W., Jeong, S. Y., Sjodt, M., McComb, R., Ho, C. L., Retterer, C., Gharaibeh, D., Zamani, R., Soloveva, V., Bavari, S., Levitin, A., West, J., Bradley, K. A., Clubb, R. T., Cohen, S. N., Gupta, V., & Martchenko, M. (2015). Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting. Scientific reports, 5, 13476.
[7] Martchenko Shilman, M., Bartolo, G., Alameh, S., Peterson, J. W., Lawrence, W. S., Peel, J. E., Sivasubramani, S. K., Beasley, D. W. C., Cote, C. K., Demons, S. T., Halasahoris, S. A., Miller, L. L., Klimko, C. P., Shoe, J. L., Fetterer, D. P., McComb, R., Ho, C. C., Bradley, K. A., Hartmann, S., Cheng, L. W., … West, J. (2021). In Vivo Activity of Repurposed Amodiaquine as a Host-Targeting Therapy for the Treatment of Anthrax. ACS infectious diseases, 7(8), 2176–2191.