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Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

ABSTRACT: Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound NEU-1090, with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.

SUBMITTER: Klug DM

PROVIDER: S-EPMC7496307 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

Klug Dana M DM Diaz-Gonzalez Rosario R DeLano Travis J TJ Mavrogiannaki Eftychia M EM Buskes Melissa J MJ Dalton Raeann M RM Fisher John K JK Schneider Katherine M KM Hilborne Vivian V Fritsche Melanie G MG Simpson Quillon J QJ Tear Westley F WF Devine William G WG Pérez-Moreno Guiomar G Ceballos-Pérez Gloria G García-Hernández Raquel R Bosch-Navarrete Cristina C Ruiz-Pérez Luis Miguel LM Gamarro Francisco F González-Pacanowska Dolores D Martinez-Martinez Maria Santos MS Manzano-Chinchon Pilar P Navarro Miguel M Pollastri Michael P MP Ferrins Lori L

RSC medicinal chemistry 20200710 8

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound <b>NEU-1090</b>, with a particular focus on improvement of absorption, d ...[more]

PMID: 33479690

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Project description:The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.

Dataset Information

Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

Publications

Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

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