4‑Substituted Benzenesulfonamides Incorporating Bi/Tricyclic Moieties Act as Potent and Isoform-Selective Carbonic Anhydrase II/IX Inhibitors

As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (<b>4</b>–<b>6</b>) 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

4‑Substituted Benzenesulfonamides Incorporating Bi/Tricyclic Moieties Act as Potent and Isoform-Selective Carbonic Anhydrase II/IX Inhibitors

As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (<b>4</b>–<b>6</b>) 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

4‑Substituted Benzenesulfonamides Incorporating Bi/Tricyclic Moieties Act as Potent and Isoform-Selective Carbonic Anhydrase II/IX Inhibitors

As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (<b>4</b>–<b>6</b>) 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

4‑Substituted Benzenesulfonamides Incorporating Bi/Tricyclic Moieties Act as Potent and Isoform-Selective Carbonic Anhydrase II/IX Inhibitors

As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (<b>4</b>–<b>6</b>) 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

4‑Substituted Benzenesulfonamides Incorporating Bi/Tricyclic Moieties Act as Potent and Isoform-Selective Carbonic Anhydrase II/IX Inhibitors

As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (<b>4</b>–<b>6</b>) 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

Benzofuroxane Derivatives as Multi-Effective Agents for the Treatment of Cardiovascular Diabetic Complications. Synthesis, Functional Evaluation, and Molecular Modeling Studies

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, <b>5a–k,m</b>, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, <b>5a–k,m</b> showed additional NO donor and antioxidant properties, thus emerging as novel multi-effective compounds. The benzyloxy derivative <b>5a</b>, 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

Tricyclic Sulfonamides Incorporating Benzothiopyrano[4,3‑<i>c</i>]pyrazole and Pyridothiopyrano[4,3‑<i>c</i>]pyrazole Effectively Inhibit α- and β‑Carbonic Anhydrase: X‑ray Crystallography and Solution Investigations on 15 Isoforms

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides <b>3a</b>–<b>e</b> were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides <b>3</b> was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib

Structure-Based Optimization of Tyrosine Kinase Inhibitor <b>CLM3</b>. Design, Synthesis, Functional Evaluation, and Molecular Modeling Studies.

Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo­[3,4-<i>d</i>]­pyrimidine derivatives, <b>8a</b>–<b>g</b>, <b>9a</b>–<b>g</b>, and <b>10a</b>–<b>g</b>, designed exploiting a structure-based optimization of the previously developed inhibitor <b>CLM3</b>. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds <b>8b</b>, <b>9c</b>, and <b>10c</b> proved to block the kinase activity of the mutant RET^V804L, which still lacks effective inhibitors

Deepening the Topology of the Translocator Protein Binding Site by Novel <i>N</i>,<i>N</i>‑Dialkyl-2-arylindol-3-ylglyoxylamides

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 (<b>8</b>–<b>16</b>) or different 2-aryl moieties, namely, 3-thienyl, <i>p</i>-biphenyl, 2-naphthyl (<b>23</b>–<b>35</b>), were synthesized and biologically evaluated, some of them showing <i>K</i>_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 L1 pocket of the TSPO binding site. Docking simulations were performed on the most potent compound of the present series (<b>29</b>) 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

Phenylpyrazolo[1,5‑<i>a</i>]quinazolin-5(4<i>H</i>)‑one: A Suitable Scaffold for the Development of Noncamptothecin Topoisomerase I (Top1) Inhibitors

In search for a novel chemotype to develop topoisomerase I (Top1) inhibitors, the pyrazolo­[1,5-<i>a</i>]­quinazoline nucleus, structurally related to the indenoisoquinoline system precursor of well-known Top1 poisons, was variously decorated (i.e., a substituted phenyl ring at 2- or 3-position, a protonable side chain at 4- or 5-position), affording a number of Top1 inhibitors with cleavage patterns common to CPT and MJ-III-65. SARs data were rationalized by means of an advanced docking protocol