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.
N-Desethyl amodiaquine是一种抗寄生虫药物，对疟原虫菌株V1/S和3D7具有抑制作用，其IC50值分别为97nM和25nM[1]。N-Desethyl amodiaquine是抗疟药物阿莫地喹的主要代谢产物，由细胞色素P450 2C8同工酶催化生成[2]。N-Desethyl amodiaquine对恶性疟原虫（Plasmodium falciparum）具有很高的活性，并且可以与阿莫地喹产生协同作用，通常用于疟疾相关研究[3-4]。
在体外实验中，N-Desethyl amodiaquine显著阻断了埃博拉病毒在Huh 7和Vero E6细胞系中的复制，其IC50值分别为2.8μM和11μM[5]。用N-Desethyl amodiaquine（8、16、33或66μM）处理RAW264.7细胞1小时，再用500ng/mL保护性抗原（PA)+ 500ng/mL致死因子( LF)处理6h，以剂量依赖的方式抑制了蛋白酶B的活性，并减少了毒素介导的细胞毒性[6]。
在体内实验中，在Sprague-Dawley大鼠模型中，静脉注射N-Desethyl amodiaquine（3、6mg/kg）可通过抑制致死因子（LF）进入细胞质而抑制LF-PA诱导的死亡[6]。此外，口服给予N-Desethyl amodiaquine（每12小时一次，连续5天，剂量为5、10和50mg/kg）可保护感染炭疽芽孢杆菌孢子的小鼠，但随着N-Desethyl amodiaquine剂量的增加，生存时间会缩短[7]。