1420290-88-5Relevant articles and documents
Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection
Shamim, Khalida,Xu, Miao,Hu, Xin,Lee, Emily M,Lu, Xiao,Huang, Ruili,Shah, Pranav,Xu, Xin,Chen, Catherine Z.,Shen, Min,Guo, Hui,Chen, Lu,Itkin, Zina,Eastman, Richard T.,Shinn, Paul,Klumpp-Thomas, Carleen,Michael, Sam,Simeonov, Anton,Lo, Donald C.,Ming, Guo-li,Song, Hongjun,Tang, Hengli,Zheng, Wei,Huang, Wenwei
supporting information, (2021/03/30)
Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2′-OMe and 2′-H substitutions were also advantageous. We found that the 4′-NO2 substituent can be replaced with a 4′-CN or 4′-CF3 substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.
TREATMENT OF ENDOMETRIOSIS AND NICLOSAMIDE DERIVATIVES
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Paragraph 00171, (2018/01/17)
Niclosamide is an effective therapeutic medicament for the treatment of endometriosis. Niclosamide treatment can reduce the size of endometrioid lesions and reduce cell proliferation in the lesions. Niclosamide treatment can result in the inhibition of proteins and genes associated with inflammatory signaling, including those associated with NFKB and STATS activation, but without altering the expression of steroid hormone receptors. Niclosamide can be effective in reducing the growth of endometrioid lesions in female mice without impairing their ability to become pregnant and without negative effect on gestation and offspring. The invention herein is useful in treating symptoms associated with endometriosis, such as reducing the growth of lesions of the endometrium, without disrupting normal reproductive function in females. The invention also relates to derivatives of niclosamide having improved solubility and enhanced efficacy.
Discovery of O-alkylamino-tethered niclosamide derivatives as potent and orally bioavailable anticancer agents
Chen, Haijun,Yang, Zhengduo,Ding, Chunyong,Chu, Lili,Zhang, Yusong,Terry, Kristin,Liu, Huiling,Shen, Qiang,Zhou, Jia
supporting information, p. 180 - 185 (2013/03/29)
Niclosamide has been identified to potently inhibit the activation, nuclear translocation, and transactivation of STAT3. Nevertheless, the poor aqueous solubility and bioavailability of niclosamide have hindered its further clinical development for cancer therapy. To discover new molecules with enhanced druglike properties, a series of novel O-alkylamino-tethered derivatives of niclosamide have been designed, synthesized, and biologically evaluated. Among them, compound 11 (HJC0152) has been demonstrated to significantly suppress MDA-MB-231 xenograft tumor growth in vivo (ip and po), indicating its great potential as efficacious and orally bioavailable therapeutics for human cancer.
