N-Desethyl amodiaquineは抗寄生虫の薬剤であり、株V1/Sと3D7に阻害作用を持ち、IC50値はそれぞれ97nMと25nMである[1]。N-Desethyl amodiaquineは抗マラリア化合物minodiaquineの主な代謝物であり、サイトクロムP450アイソフォーム2C8の作用で産生される[2]。N-Desethyl amodiaquineは熱帯熱マラリア原虫に対する活性が高く、amodiaquineと相乗効果を生み出し、主にマラリアの研究に使われる[3-4]。
体外では、N-Desethyl amodiaquineの処理は、エボラウイルスに感染したHuh 7とVero E6細胞株の両方で、ウイルス複製を著しく遮断し、IC50値は2.8μMと11μMである[5]。N-Desethyl amodiaquine (8、16、33または66μM)でRAW264.7細胞を1時間処理し、更に500ng/mLの保護性抗原(PA)+ 500ng/mLの致死因子(LF)で6時間投与した結果、用量依存的にプロテイナーゼBの活性を阻害し、毒素媒介の細胞毒性を減らした[6]。
体内で、N-Desethyl amodiaquine (3, 6mg/kg)の静脈内注射は、Sprague−Dawleyラットモデルで、LFの細胞質への進入を阻害することで、PA-LF誘発の死亡を阻害する[6]。5, 10と50mg/kgのN-Desethyl amodiaquineを5日間、12時間ごとに経口投与した結果、B. 炭疽菌胞子感染のマウスを保護し、N-Desethyl amodiaquineの用量が増加すると同時に、生存期間は減る[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.