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As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (4-6) featuring the primary benzenesulfonamide moiety linked to bi/tricyclic scaffolds were investigated. Highly effective inhibitors against the target tumor-associated hCA IX (low nanomolar/ subnanomolar potency levels) showing significant functional selectivity profile toward hCA I, II, and IV isozymes were identified. Molecular docking studies clarified the reasons behind the activity and selectivity of the new compounds.

The gasotransmitter hydrogen sulfide (H2S) is an important tuner of the cardiovascular homeostasis, and its deficiency is etiologically associated with a number of cardiovascular diseases. Therefore, the research of original moieties able to release H2S represents a timely issue for drug discovery. In this work, we developed a collection of iminothioethers (ITEs), exhibiting H2S-releasing properties and producing vasorelaxing effects on rat aortic rings. Derivatives 4 and 11, selected as representative of slow and fast rate H2S donors, respectively, produced a complete recovery of the basal coronary flow, reverting the AngII-induced effects in isolated rat hearts. In addition, studies on human aortic smooth muscle cells (HASMCs) demonstrated membrane hyperpolarizing effects, well related to the intracellular generation of H2S. Taken together, the results obtained support ITEs 4 and 11 as new pharmacological tools, as well as effective and innovative H2S donors for cardiovascular drug discovery.

The quinazoline class was exploited to search for a new translocator protein (TSPO) fluorescent probe endowed with improved affinity and residence time (RT). Computational studies on an "in-house" collection of quinazoline derivatives, featuring highly steric demanding groups at the amide nitrogen, suggested that, despite their molecular extension, these ligands are still easily lodged in the TSPO binding site. Binding assays supported this hypothesis, highlighting a low nanomolar/subnanomolar affinity of these ligands, together with a higher RT of the representative compound 11 with respect to our previously reported indole-based fluorescent probe. Thanks to the amenability of the amide nitrogen atom to be substituted with bulky groups, we developed quinazoline-based imaging tools by fluorescently labeling the scaffold at this position. Probes with relevant TSPO affinity, favorable spectroscopic properties, and improved RT were identified. The results from fluorescence microscopy showed that these probes specifically labeled the TSPO at the mitochondrial level in the U343 cell line.

As a continuation of our studies on 2-phenylindol-3-ylglyoxylamides as potent and selective translocator protein (TSPO) ligands, two subsets of novel derivatives, featuring hydrophilic group (OH, NH2, COOH) at the para-position of the pendent 2-phenyl ring (8-16) or different 2-aryl moieties, namely, 3-thienyl, p-biphenyl, 2-naphthyl (23-35), were synthesized and biologically evaluated, some of them showing K-i values in the subnanomolar range and the 2-naphthyl group performance being the best. The resulting SARs confirmed the key role played by interactions taking place between ligands and the lipophilic Li pocket of the TSPO binding site. Docking simulations were performed on the most potent compound of the present series (29) exploiting the recently available 3D structures of TSPO bound to its standard ligand (PK11195). Our theoretical model was fully consistent with SARs of the newly investigated as well of the previously reported 2-phenylindol-3-ylglyoxylamide derivatives.

Diabetes mellitus is the major risk factor for cardiovascular disorders. Aldose reductase, the rate-limiting enzyme of the polyol pathway, plays a key role in the pathogenesis of diabetic complications. Accordingly, inhibition of this enzyme is emerging as a major therapeutic strategy for the treatment of hyperglycemia-induced cardiovascular pathologies. In this study, we describe a series of 5(6)-substituted benzofuroxane derivatives, 5a-k,m, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, 5a-k,m showed additional NO donor and antioxidant properties, thus emerging as novel multi-effective compounds. The benzyloxy derivative 5a, the most promising of the whole series, showed a well-balanced, multifunctional profile consisting of submicromolar ALR2 inhibitory efficacy (IC50 = 0.99 ± 0.02 μM), significant and spontaneous NO generation properties, and excellent hydroxyl radical scavenging activity. Computational studies of the novel compounds clarified the aldose reductase inhibitory profile observed, thus rationalizing structure-activity relationships of the whole series. © 2012 American Chemical Society.

In an effort to identify novel ligands possessing high affinity and selectivity for the A(2B) AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A(1) AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A(2B) AR, no affinity at A(3) AR, and various degrees of selectivity toward A(1) and A(2A) ARs. Investigation of a new series featuring modified substituents at the 10-position (4'-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A(2B) AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A(2A) AR, conferring high A(2B)/A(2A) AR selectivity. Derivative 13 (X = Cl, R = C(6)H(5)) is the most potent and selective compound, with an IC(50) of 3.10 nM at A(2B) AR and no affinity at A(1), A(2A), and A(3) ARs.