Synthesis and in silico and in vitro evaluation of trimethoxy-benzamides designed as anti-prion derivatives

Journal Article · Sun Dec 15 04:00:00 EST 2019 · Medicinal Chemistry Research (Print)

DOI:https://doi.org/10.1007/S00044-019-02441-2· OSTI ID:22936155

Conceição, Raissa A.; Ascari, Lucas M.; Ferreira, Natália C.; Goes, Carolina F. ^[1]; Matos, Carolina O.; Pinheiro, Anderson S. ^[2]; Alves, Marina A. ^[3]; Souza, Alessandra M. T. ^[1]; Maia, Rodolfo C. ^[4]; Caughey, Byron ^[5]; Cordeiro, Yraima

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1. Federal University of Rio de Janeiro (UFRJ), Faculty of Pharmacy (Brazil)
2. Federal University of Rio de Janeiro (UFRJ), Department of Biochemistry, Institute of Chemistry (Brazil)
3. Federal University of Rio de Janeiro (UFRJ), Laboratory for the Support of Technological Development (LADETEC), Institute of Chemistry (Brazil)
4. Federal University of Rio de Janeiro (UFRJ), Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences (Brazil)
5. National Institutes of Health, Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (United States)

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are neurodegenerative disorders which affect mammals, including the human species, and arise after the conversion of the monomeric cellular prion protein (PrP{sup C}) into the aggregated scrapie form (PrP{sup Sc}). There is no therapy to treat TSEs and the identification of compounds that bind PrP{sup C}, preventing its conversion into PrP{sup Sc}, is a viable therapeutic strategy. We designed and synthesized six novel trimethoxy-benzamide compounds as anti-prion drug candidates. Molecular docking analyses predicted that all the derivatives bind to a hotspot region located in the PrP globular domain with very similar spatial orientation and interaction mode. Although none of the analogs inhibited in vitro-aggregation of recombinant PrP (rPrP) in a cell-free conversion assay, the RT-QuIC, compound 8a accelerated rPrP conversion into PrP{sup Sc}-like species. STD-NMR and ITC analyses indicated that both 8a and 8b bind to rPrP{sup 90–231}. These analogs were toxic to PrP{sup Sc}-infected cell lines, hence we could not assess their anti-prion activity by using this cellular approach, although this toxicity was cell line-dependent. These results point out that the 4-amino-quinoline trimethoxy-benzamide scaffold described herein represents a novel chemical pattern useful as a starting point for future structural optimization in the design of PrP ligands with improved affinity and safety profiles.

• OSTI ID: 22936155
• Journal Information: Medicinal Chemistry Research (Print), Journal Name: Medicinal Chemistry Research (Print) Journal Issue: 12 Vol. 28; ISSN 1054-2523
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
DRUGS
IN VITRO
MAMMALS
PROTEINS
QUINOLINES
SYNTHESIS
THERAPY
TOXICITY