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Eur J Med Chem. 2018 May 25;152:53-64. doi: 10.1016/j.ejmech.2018.04.027. Epub 2018 Apr 13.

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.

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Department of Pharmacy - University of Chieti "G. d'Annunzio", Italy. Electronic address:
Department of Pharmacy - University of Chieti "G. d'Annunzio", Italy.
Department of Biomedical Sciences and Human Oncology, Medical School - University of Bari "Aldo Moro", Italy.
Department of Medical, Oral and Biotechnological Sciences, Centro Scienze dell'Invecchiamento e Medicina Traslazionale (Ce.SI-MeT), University "G. d'Annunzio" Chieti-Pescara, Italy.


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.


Acetamidine; Anticancer; Docking; Glioma; Inhibitors; Nitric oxide; Nitric oxide synthases; Synthesis

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