Derivatives of 1,2,4-triazole imines acting as dual iNOS and tumor cell growth inhibitors

• Published in: Bioorganic chemistry 2020-10, Vol.103, p.104128-104128, Article 104128
• Main Authors: Guillon, Christophe, Vetrano, Anna M., Saxena, Jaya, Hunter, Angela, Verderone, Geraldine, Finetti, Thomas M., Wisnoski, Jeffrey, DeMatteo, Peter W., Rapp, Robert D., Heindel, Ned D., Joseph, Laurie B., Heck, Diane E., Laskin, Jeffrey D.
• Format: Article
• Language: English
• Subjects: Animals; Anti-neoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Growth Inhibitors - chemical synthesis; Growth Inhibitors - chemistry; Growth Inhibitors - pharmacology; HeLa; HT-29; Imines - chemical synthesis; Imines - chemistry; Imines - pharmacology; iNOS inhibitors; Mice; Molecular Structure; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Nitric oxide synthase; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Nitrofurantoin; Nitrofurazone; PAM212; PC3; Structure-Activity Relationship; Triazole; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104128

[Display omitted] •Novel 1,2,4-triazole imines were synthesized and evaluated as iNOS inhibitors.•Some also showed inhibitory growth properties against selected cancer cell lines.•The ones designed as nitrofurantoin mimics showed the best anti-neoplastic activity. A set of 4-(R2-imino)-3-mercapto-5-(R1)-4H-1,2,4-triazoles derivatives were synthesized, characterized and evaluated for their ability to inhibit nitric oxide (NO) production in PAM212 mouse keratinocytes, which led to the discovery and the subsequent evaluation of their growth inhibitory cytotoxic potency toward that same mouse cell line together with a number of human cells lines (PC3, HT-29 and HeLa). Some limited SAR could be established for both NO production inhibition potency and growth inhibition cytotoxicity. Noticeably, the compounds designed to be nitrofurantoin mimics were the most potent anti-neoplastic agents.