[Show abstract][Hide abstract] ABSTRACT: Tyrosinase is a copper-containing enzyme widely distributed in nature, involved in the biosynthesis of melanin whose role is to protect the skin from ultraviolet damage. A great interest has been shown on the melanin involvement in malignant melanoma and other carcinogenetic processes. These phenomena have encouraged the research of tyrosinase inhibitors useful in therapeutic field as well as in foods and cosmetics to prevent browning. The idea was to screen our "in house" database to select suitable lead compounds for the discovery of potential drug-inhibiting enzyme. The obtained biological results demonstrated that compounds containing 4-fluorobenzyl moiety at N - 1 position of indole system showed the best activity. In addition, the role of the portion linked to the carbonyl group at C - 3 was discussed. A Lineweaver-Burk kinetic analysis of the most active indoles, CHI 1043 and derivative 4, showed a mixed-type inhibition in the presence of l-3,4-dihydroxyphenylalanine (l-DOPA) as substrate.
No preview · Article · Mar 2015 · Journal of Enzyme Inhibition and Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Carbon nanotubes have attracted particular attention in antiviral therapy and recently have been explored as HIV inhibitors through structure-based design. In order to prove their in vitro ability to interact with viral enzymes and to act as HIV inhibitors, we have studied the antiviral potentiality of highly hydrophilic and dispersible carboxylated multi-walled carbon nanotubes (ox-MWCNT) and the activity exerted by the same nanomaterial bearing antiretroviral drugs and hydrophilic functionalities. The antiretroviral drugs chosen for this study were two newly synthesized benzimidazolones, CHI360 and CHI415, belonging to a series of active non-nucleoside reverse transcriptase inhibitors (RTI), and lamivudine (3TC), a known antiretroviral nucleoside agent, currently used in anti-HIV therapy. From this study, the physicochemical properties of these nanomaterials, namely hydrophilicity and dispersibility, emerged as the most relevant features able to control the antiviral activity. The more hydrophilic and dispersible oxidized samples, ox-MWCNT and MWCNT-C-CHI360, showed the best results with IC50 values of 11.43 mu g/mL and 4.56 mu g/mL, respectively.
[Show abstract][Hide abstract] ABSTRACT: In an effort to improve our knowledge about structure–affinity relationships (SARs) for a class of 3-substituted-indole derivatives as GluN2B-containing N-methyl-D-aspartate-type receptor (NMDAR) ligands, we herein describe the design, synthesis, and preliminary screening of a new series of molecules. The in vitro determination of binding affinities suggested that 5-hydroxy- and 6-hydroxyindole derivatives 12 and 13 were active ligands. Generally, the novel compounds proved to be less potent than their homologs previously reported as promising neuroprotective agents. In fact, our lead compound 3-(4-benzylpiperidin-1-yl)-1-(5-hydroxy-1H-indol-3-yl)ethan-1-one (2) was about 10-fold more active than the new propan-1-one derivative (12). To rationalize the low potency of the new analog 12, docking studies were also performed and the in silico results were consistent with the in vitro data.
No preview · Article · Aug 2014 · Archiv der Pharmazie
[Show abstract][Hide abstract] ABSTRACT: HIV-1 Integrase (IN) represents a very attractive pharmacological target for the development of new and more efficient drugs. Recently, an allosteric inhibitory approach also emerged, that targets the interaction between IN and cellular cofactors, such as LEDGF/p75. Small molecules based on the diketoacid pharmachophore were studied for their ability to inhibit at the same time integration and IN-LEDGF/p75 interaction (dual inhibitors): in this study, we evaluated three indole diketoacid derivatives and their magnesium(II) complexes for their ability to act as dual inhibitors. Effectively, the metal complexes exhibited IN inhibition potency in low nanomolar/micromolar concentration range; both the complexes and the free ligands are also able to inhibit the IN-LEDGF/p75 interaction at low μM values. Moreover, these magnesium compounds showed good antiviral activity, suggesting the possibility to exploit metal coordination for the design of new antivirals.
Full-text · Article · Mar 2014 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Therapeutic treatment of AIDS is recently characterized by a crescent effort towards the identification of multiple ligands able to target different steps of HIV-1 life cycle. Taking into consideration our previously obtained SAR information and combining some important chemical structural features we report herein the synthesis of novel benzyl-indole derivatives as anti-HIV agents. Through this work we identified new dual target small molecules able to inhibit both IN-LEDGF/p75 interaction and the IN strand-transfer step considered as two crucial phases of viral life cycle.
No preview · Article · Feb 2014 · Bioorganic & medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: A series of novel N1-aryl-2-arylthioacetamido-benzimidazoles were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Some of them proved to be effective in inhibiting HIV-1 replication at submicromolar and nanomolar concentration acting as HIV-1 non-nucleoside RT inhibitors (NNRTIs), with low cytotoxicity. The preliminary structure-activity relationship (SAR) of these new derivatives was discussed and rationalized by docking studies.
No preview · Article · Dec 2013 · Bioorganic & medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [(3)H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50=5.5nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel 'dual target' neuroprotective agents.
[Show abstract][Hide abstract] ABSTRACT: Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward σ2 receptor (Ki values of 10nM and 20nM, respectively). Thus, in this case the discovery of new σ2 receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors.
No preview · Article · Nov 2013 · Bioorganic & medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: Among the different mammalian isoforms of Carbonic Anhydrase, the hCA VII is mainly expressed in the brain where it is involved in several neurological diseases. Thereby hCA VII has been validated as an attractive target for the discovery of selective inhibitors for the treatment of epilepsy and neurological pain. To identify new chemical entities as carbonic anhydrase inhibitors (CAIs) targeting hCA VII, we used a structure-based approach. By means of LigandScout software we built pharmacophore models from crystal structures of two well-known CAIs in complex with hCA VII. A merged pharmacophore hypothesis has been obtained. Subsequently, a focused library of compounds was screened against pharmacophore model and the most interesting hits were docked into the crystal structure of hCA VII. As a result, we identified new compounds displaying significant CA inhibitory effects in the nanomolar range.
No preview · Article · Nov 2013 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: The disruption of crucial interactions between HIV-1 Integrase and cellular cofactor LEDGF/p75 represents an emerging approach for the design and development of new antiretroviral agents. In this study we report the successful application of a structure-based virtual screening strategy for the discovery of natural hit structures able to inhibit Integrase-LEDGF/p75 interaction. The application of sequential filters (drug-likeness, 3D-pharmacophore mapping, docking, molecular dynamics simulations) yielded a hit list of compounds, out of which 9 were tested in the in vitro AlphaScreen assays and 8 exhibited a detectable inhibition of the interaction between the two proteins. The best inhibitors belong to different chemical classes and could be represent a good starting point for further optimization and structure-activity relationship studies.
No preview · Article · Aug 2013 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Abstract In continuation of our research efforts toward the identification and optimization for novel inhibitors of interaction between human immunodeficiency virus type 1 integrase and cellular cofactor LEDGF/p75, we designed and synthesized a new series of 4-benzylindole derivatives. Most of the title compounds proved to be able to block this protein-protein interaction (PPI), with a percentage ranging from 30% to 90% at 100 µM. The most promising derivative was compound 10b showing IC50 value of 6.41 µM. The main structure-activity relationships (SAR) are discussed and rationalized by docking studies.
No preview · Article · Jul 2013 · Journal of Enzyme Inhibition and Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Several indole derivatives, that were highly potent ligands of GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptor, also demonstrated antioxidant properties in ABTS method. In particular, the 2-(4-benzylpiperidin-1-yl)-1-(5-hydroxy-1H-indol-3-yl)ethanone (1) proved to be a dual-effective neuroprotective agent. With the aim to increase the antioxidant properties we added a catechol moiety onto piperidine moiety. The designed hybrid derivative 3,4-dihydroxy-N-[1-[2-(5-hydroxy-1H-indol-3-yl)-2-oxoethyl]piperidin-4-yl]benzamide (10) was the most effective antioxidant agent (>94.1±0.1% of inhibition at 17μM) and showed GluN2B/NMDA receptor affinity at low micromolar concentration (IC50 0.66μM). By means of computational studies we explored the effect of the presence of this antioxidant fragment during the recognition process to binding pocket.
[Show abstract][Hide abstract] ABSTRACT: In the course of the identification of new indole derivatives targeting GluN2B-subunit-containing N-methyl-D-Aspartate (NMDA) receptor, the (N-1H-indol-6-methanesulfonamide-3-yl)-2-(4-benzylpiperidin-1-yl)ethanone (10b) was identified as a potent ligand for this NMDA receptor subunit. It displays very high binding affinity (IC50 value of 8.9 nmol) for displacement of [3H]-ifenprodil thus showing improved potency with respect to the previously reported analogues as confirmed by functional assay. This finding was consistent with the docking pose of compound 10b within the binding pocket localized in the GluN1-GluN2B subunit interface of NMDA receptor tetraheteromeric complex.
Full-text · Article · Nov 2012 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: We recently identified a series of indole derivatives as active inhibitors of IN-LEDGF/p75 interaction through structure-based pharmacophore models generated from the crystal structure of dimeric catalytic core domain (CCD) of HIV-1 IN in complex with the LEDGF integrase binding domain (IBD). In this paper we used the fragment hopping approach to design small molecules able to prevent the IN-LEDGF/p75 interaction. By means of the proposed approach, we designed novel non-peptidyl compounds that mimic the biological function of some IBD residues and in particular the LEDGF hot spot residues Ile365 and Asp366. The biological results confirmed the importance of several structural requirements for the inhibitory effects of this class of compounds.
No preview · Article · Jul 2012 · Journal of Enzyme Inhibition and Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: A series of arylsulfonamides has been synthesized and investigated for the inhibition of some selected human carbonic anhydrase isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV) (K(i) values from 4.8 to 61.7 nM), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. On the basis of biochemical data, we herein discussed structure-affinity relationships for this series of arylsulfonamides, suggesting a key role for alkoxy substituents in CA inhibition. Furthermore, X-ray crystal structures of complexes of two active inhibitors (I and 2a) with hCA II allowed us to elucidate the main interactions between the inhibitor and specific amino acid residues within the catalytic site.
No preview · Article · Mar 2012 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: In a previous paper we identified several 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-sulfonamides that displayed inhibitory effects toward selected carbonic anhydrase isozymes at micromolar concentration. In order to deepen the structure-activity relationships (SARs) and identify novel compounds with improved activity, we synthesized a series of monomethoxy analogues of the previously investigated dimethoxy derivatives. The evaluation of biological profile has been focused on in vitro effects against several CA isoforms. The new monomethoxy derivatives showed higher hCA inhibitory effects against several isoforms compared to the dimethoxy analogues. Particularly, some of these compounds (e.g., 1b and 1h) showed low nanomolar K(I) values and excellent selectivity for hCA IX and hCA XIV versus hCA I and II inhibition.
No preview · Article · Dec 2011 · Bioorganic & medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). In recent years our research group has been engaged in the stucture-function study of this enzyme and in the development of some three-dimensional pharmacophore models which have led to the identification of a large series of potent HIV-1 integrase strand-transfer inhibitors (INSTIs) bearing an indole core. To gain a better understanding of the structure-activity relationships (SARs), herein we report the design and microwave-assisted synthesis of a novel series of 1-H-benzylindole derivatives.