A thiazepino[4,5-a]benzimidazole derivative hampers the RNA replication of Eurasian serotypes of foot-and-mouth disease virus.

The stamping-out policy for the control of foot-and-mouth disease virus (FMDV) in countries that are free from FMD without vaccination has a dramatic socio-economic impact, huge animal welfare issues and may result in the loss of farm animal genetic resources. As an alternative to pre-emptive culling or emergency vaccination we further explore the possibility to use antiviral drugs in the event of an FMD outbreak. In the present study, we tested the in vitro cytotoxicity and anti-FMDV activity of 1,2,4,5-tetrahydro-[1,4]thiazepino[4,5-a]benzimidazole.

Diketoacid chelating ligands as dual inhibitors of HIV-1 integration process.

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.

A new potential approach to block HIV-1 replication via protein-protein interaction and strand-transfer inhibition.

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.

Design and synthesis of N₁-aryl-benzimidazoles 2-substituted as novel HIV-1 non-nucleoside reverse transcriptase inhibitors.

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.

Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors.

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).

From NMDA receptor antagonists to discovery of selective σ₂ receptor ligands.

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.

Structure-based screening for the discovery of new carbonic anhydrase VII inhibitors.

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.

Synthesis and biological evaluation of novel antiviral agents as protein-protein interaction inhibitors.

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.

Indole derivatives as dual-effective agents for the treatment of neurodegenerative diseases: synthesis, biological evaluation, and molecular modeling studies.

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.

Insight into the fundamental interactions between LEDGF binding site inhibitors and integrase combining docking and molecular dynamics simulations.

In recent years, HIV-1 integrase (IN) has emerged as an attractive target for novel anti-AIDS agents. In particular, nonactive-site-binding IN inhibitors would display synergy with current strand-transfer-specific IN inhibitors and other antiretroviral drugs in clinical use. An effective allosteric inhibitory approach would be the disruption of protein-protein interaction (PPI) between IN and cellular cofactors, such as LEDGF/p75.

Synthesis and biological characterization of 3-substituted 1H-indoles as ligands of GluN2B-containing N-methyl-D-aspartate receptors. Part 2.

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 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.

Fragment hopping approach directed at design of HIV IN-LEDGF/p75 interaction inhibitors.

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.

New AMPA antagonists in epilepsy.

Introduction: Epilepsy is a common neurological disorder; however, its therapy is not satisfactory because a large number of patients suffer from refractory seizures and/or has a low quality of life due to antiepileptic drug (AED) side effects. Glutamate is the major excitatory neurotransmitter in the brain, AMPA receptors (AMPARs) represent a validated target for AEDs' development. Evidences support their role during seizures and neurodegeneration.

Synthesis, structure-activity relationship studies, and X-ray crystallographic analysis of arylsulfonamides as potent carbonic anhydrase inhibitors.

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.

Glutamatergic neurotransmission as molecular target of new anticonvulsants.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) controlling physiological processes as learning and memory. However, the overactivation of glutamatergic neurotransmission is often related to various CNS chronic and acute diseases (epilepsy, ischaemia, Parkinson, etc.).

Synthesis and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-D-aspartate receptors.

As an extension of our studies, novel indole derivatives were rationally designed and synthesized as ligands targeted to GluN2B/NMDA receptors. The 2-(4-benzylpiperidin-1-yl)-1-(6-hydroxy-1H-indol-3-yl)ethanone (4i) and 1-(4-benzylpiperidin-1-yl)-2-(6-hydroxy-1H-indol-3-yl)ethane-1,2-dione (6i) showed high binding affinity in [3H]ifenprodil displacement assay. By computational studies, we suggested the hypothetical interactions playing a significant role during the binding process.

Synthesis and biological profile of new 1,2,3,4-tetrahydroisoquinolines as selective carbonic anhydrase inhibitors.

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.

Microwave assisted organic synthesis (MAOS) of small molecules as potential HIV-1 integrase inhibitors.

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.

4-[1-(4-Fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid as a prototype to develop dual inhibitors of HIV-1 integration process.

In recent years several potent HIV-1 integrase (IN) inhibitors have been identified and after the successful clinical use of raltegravir, they have gained a definitive place in the treatment of HIV-1 infection. Yet, there is a continuous effort to design newer inhibitors that target different steps in the integration process. Furthermore, the increased understanding of IN structural biology has opened novel approaches to inhibit IN, such as targeting its multimerization or interaction with cellular cofactors.

3-[2-(1H-1,3-Benzodiazol-2-yl)eth-yl]-1,3-oxazolidin-2-one.

In the title compound, C(12)H(13)N(3)O(2), the dihedral angle between the oxazolone ring and the benzimidazole unit is 45.0 (5)°, exhibiting a staggered conformation at the Cα-Cβ bond. In the crystal, a strong N-H⋯N hydrogen bond links the mol-ecules into a C(4) chain along the c axis while a C-H⋯O hydrogen-bonding inter-action generates a C(5) chain along the a axis, i.

Inhibition of the interaction between HIV-1 integrase and its cofactor LEDGF/p75: a promising approach in anti-retroviral therapy.

Although 25 compounds are currently licensed as anti-HIV drugs, the development of multidrug-resistant viruses, as well as their severe side effects, compromise their efficacy and limit treatment options. The search for new targets in order to cure AIDS has revealed that the inhibition of some protein-protein interactions in the HIV life cycle may provide an important new approach to fight this disease. The interaction between HIV-1 integrase (IN) and Lens Epithelium-Derived Growth Factor (LEDGF/p75) has increasingly gained attention as a valuable target for a novel anti-retroviral strategy.

Inhibitors of the interactions between HIV-1 IN and the cofactor LEDGF/p75.

The replication cycle of human immunodeficiency virus type 1 (HIV-1) is a complex multistep process that depends on both viral and host cell factors. The nuclear protein lens epithelium-derived growth factor (LEDGF/p75) is a multidomain protein, present in host cells, which plays an important role in the integration process. LEDGF/p75 not only binds HIV-1 integrase (IN) at its IN binding domain (IBD) but also contains several motifs that function in DNA and chromatin binding.

Structural basis for the interaction between carbonic anhydrase and 1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamides.

Isoquinolinesulfonamides inhibit human carbonic anhydrases (hCAs) and display selectivity toward therapeutically relevant isozymes. The crystal structure of hCA II in complex with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamide revealed unusual inhibitor binding. Structural analyses allowed for discerning the fine details of the inhibitor binding mode to the active site, thus providing clues for the future design of even more selective inhibitors for druggable isoforms such as the cancer associated hCA IX and neuronal hCA VII.

HIV-1 integrase strand-transfer inhibitors: design, synthesis and molecular modeling investigation.

This study is focused on a new series of benzylindole derivatives with various substituents at the benzene-fused ring, suggested by our 3D pharmacophore model developed for HIV-1 integrase inhibitors (INIs). All synthesized compounds proved to be active in the nanomolar range (6-35 nM) on the strand-transfer step (ST). In particular, derivative 4-[1-(4-fluorobenzyl)-5,7-dimethoxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (8e), presenting the highest best-fit value on pharmacophore model, showed a potency comparable to that of clinical INSTIs GS 9137 (1) and MK-0518 (2).

2-hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: influence of the alkylation of position 4.

We report herein the synthesis of a series of fifteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives. Alkyl and arylalkyl groups were introduced on position 4 of the basis scaffold. All the compounds presented poor inhibitory properties against HIV-1 reverse transcriptase ribonuclease H (RNase H).