Discovery of N-{3-[(ethanimidoylamino)methyl]benzyl}-l-prolinamide dihydrochloride: A new potent and selective inhibitor of the inducible nitric oxide synthase as a promising agent for the therapy of malignant glioma.

Abstract

In mammalian cells, aberrant iNOS induction may have detrimental consequences, and seems to be involved in the proliferation and progression of different tumors, such as malignant gliomas. Therefore, selective inhibition of iNOS could represent a feasible therapeutic strategy to treat these conditions. In this context, we have previously disclosed new acetamidines able to inhibit iNOS with a very high selectivity profile over eNOS or nNOS. Here we report the synthesis of a new series of compounds structurally related to the leading scaffold of N-[(3-aminomethyl)benzyl] acetamidine (1400 W), together with their in vitro activity and selectivity. Compound 39 emerged as the most promising molecule of this series, and it was ex vivo evaluated on isolated and perfused resistance arteries, confirming a high selectivity toward iNOS inhibition. Moreover, C6 rat glioma cell lines biological response to 39 was investigated, and preliminary MTT assay showed a significant decrease in cell metabolic activity of C6 rat glioma cells. Finally, results of a docking study shed light on the binding mode of 39 into NOS catalytic site.

• Authors: Cristina Maccallini, Mauro Di Matteo, Marialucia Gallorini, Monica Montagnani, Valentina Graziani, Alessandra Ammazzalorso, Pasquale Amoia, Barbara De Filippis, Sara Di Silvestre, Marialuigia Fantacuzzi, Letizia Giampietro, Maria A Potenza, Nazzareno Re, Assunta Pandolfi, Amelia Cataldi, Rosa Amoroso
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 152 Pg. 53-64 (May 25 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29689474 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amidines
• Antineoplastic Agents
• CM544
• Enzyme Inhibitors
• Proline
• NOS2 protein, human
• Nitric Oxide Synthase Type II

Topics

• Amidines
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Glioma (drug therapy, metabolism, pathology)
• Male
• Mesenteric Arteries (drug effects, metabolism)
• Molecular Docking Simulation
• Molecular Structure
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Proline (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship