Antiglioma Activity of Aryl and Amido-Aryl Acetamidine Derivatives Targeting iNOS: Synthesis and Biological Evaluation

Abstract

Nitric oxide is an important inflammation mediator with a recognized role in the development of different cancers. Gliomas are primary tumors of the central nervous system with poor prognosis, and the expression of the inducible nitric oxide synthase correlates with the degree of malignancy, changes in vascular reactivity, and neo-angiogenesis. Therefore, targeting the nitric oxide biosynthesis appears as a potential strategy to impair glioma progression. In the present work a set of aryl and amido-aryl acetamidine derivatives were synthesized to obtain new potent and selective inducible nitric oxide synthase inhibitors with improved physicochemical parameters with respect to the previously published molecules. Compound 17 emerged as the most promising inhibitor and was evaluated on C6 rat glioma cell line, showing antiproliferative effects and high selectivity over astrocytes.

New azolyl-derivatives as multitargeting agents against breast cancer and fungal infections: synthesis, biological evaluation and docking study

“…In particular, 13a chemical scaffold was modified connecting to the stereogenic centre a benzyl group instead of the phenyl one, and different bulky aromatic moieties by means of an ester, or urethane, or a thiourethane group (Figure 1, compounds 2-8). Compound 3o was modified by introducing a triazole instead of the imidazole as the aromatase haem-coordinating moiety, and inserting different substituents on the aromatic ring, similarly to the previously reported imidazolyl-piperidine sulphonamides (Figure 1, compounds [13][14][15][16][17][18][19][20]. Considering the therapeutic diversity of many azole-based compounds 13,14 and the multifactorial features of BC, it was supposed that molecules 2-8 and 13-20 could be useful to manage such a pathological condition acting as multi-target-directed ligands.…”

“…Since azole-containing molecules have demonstrated activity towards this enzyme both as substrate analogues and dimerisation inhibitors 16 and based on our ongoing efforts in the research of new molecules able to inhibit iNOS 17,18 , we evaluated compounds 2-8 and 13-20 as iNOS inhibitors, with the aim to ascertain their potential polypharmacological effects against breast cancer progression. To confirm the therapeutic potential of the most promising inhibitors of both aromatase and iNOS, they were then evaluated on a breast cancer cell line as antiproliferative and cytotoxic agents.…”

Selective Inhibitors of the Inducible Nitric Oxide Synthase as Modulators of Cell Responses in LPS-Stimulated Human Monocytes

“…As part of an ongoing project on the development of safer and potent iNOS inhibitors, we recently reported the compounds N -(3-{[(1-iminioethyl)amino]methyl}benzyl)prolinamide dihydrochloride (CM554, Figure 1 ) and 4-(ethanimidoylamino)- N -(4-fluorophenyl)benzamide hydrobromide (FAB1020, Figure 1 ) [ 14 , 15 , 16 ]. These acetamidines were designed based on the chemical structure of N -(3-(aminomethyl)benzyl)acetamidine (1400 W, Figure 1 ), a very potent and selective iNOS inhibitor patented by GlaxoSmithKline [ 17 ] which, unfortunately, never passed clinical trials.…”

A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

“…Several selective nNOS and/or iNOS inhibitors have been published to date, most of them targeting the l-Arg binding site of the enzyme oxygenase domain, which is highly conserved among the NOS isoforms. [18][19][20][21] In our continuous effort to develop selective NOS inhibitors, we have identified several acetamidines structurally related to 1400 W, a potent inhibitor of the human iNOS ( Figure 1), [22][23][24][25][26][27][28][29][30] which, however, has never passed clinical trials. In particular, we disclosed the 1-(benzhydrylamino)ethaniminium bromide (compound 1) showing high potency toward nNOS and selectivity with respect to the eNOS and iNOS (nNOS IC 50 = 0.3 μM; eNOS/ nNOS selectivity = 1166 folds; iNOS/nNOS selectivity = 100 folds).…”

“…In our continuous effort to develop selective NOS inhibitors, we have identified several acetamidines structurally related to 1400 W , a potent inhibitor of the human iNOS (Figure 1), [22–30] which, however, has never passed clinical trials. In particular, we disclosed the 1‐(benzhydrylamino)ethaniminium bromide (compound 1 ) showing high potency toward nNOS and selectivity with respect to the eNOS and iNOS (nNOS IC 50 =0.3 μM; eNOS/nNOS selectivity=1166 folds; iNOS/nNOS selectivity=100 folds) [31] .…”