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-Cß 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.e. perpendicular to the other chain.

Selective reductions of cyclic 1,3-diesters by using SmI(2) and H(2)O.

SmI(2)/H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters, and esters. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes. The ketal unit and the reaction temperature have a marked impact on the diastereoselectivity of the cyclizations. Cyclization cascades are possible when two alkenes are present in the starting cyclic diester and lead to the formation of two rings and four stereocenters with excellent stereocontrol.

New chloro,fluorobenzylindole derivatives as integrase strand-transfer inhibitors (INSTIs) and their mode of action.

The life cycle of HIV-1 requires extensive assistance from the integrase (IN) enzyme which therefore constitutes an attractive therapeutic target for the development of anti-AIDS agents. We herein report the synthesis and biological evaluation of new HIV integrase strand-transfer inhibitors (INSTIs) which proved to be also potent anti-HIV agents. The binding mode of the most representative molecules were also studied by induced-fit docking (IFD). The obtained IFD results were consistent with the mechanism of action proposed for this class of IN inhibitors, that is metal chelating/binding agents.

Selective reductions of cyclic 1,3-diesters using SmI(2) and H(2)O.

SmI(2)-H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over-reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters and esters. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron transfer to the ester carbonyl and the anomeric stabilization of the resulting radical-anion intermediate. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes.

Immunomodulatory activities of alpha lipoic acid with a special focus on its efficacy in preventing miscarriage.

INTRODUCTION: Alpha lipoic acid (ALA) is an essential mitochondrial co-factor and, as a free molecule, it can exert multi-level immunomodulatory functions. Both ALA and its reduced form, dihydrolipoic acid (DHLA), are believed to be able to chelate heavy metals, to regenerate essential antioxidants and to repair important molecules damaged by oxidation. The largest part of the effects of ALA/DHLA couple can be explained by a specific stimulatory activity on Nrf2-dependent gene transcription and by the inhibition of NF-kB activity. These features have prompted its use as a drug for several diseases. Areas covered: This article surveys the main features of ALA/DHLA and its therapeutic effects. Its complex and differentiated function cannot simply be reduced to anti-inflammatory, antioxidant and detoxifying action. We highlight its capability to finely modulate several physiological pathways when unbalanced. In particular, we focus our attention on pregnancy, in relation to ALA administration by oral route and by a new formulation for vaginal delivery, in patients with threatened miscarriage. Expert opinion: Future efforts should be devoted to explaining carefully ALA/DHLA mechanism of action to reactivate the physiological balance when modified during pregnancy. On the other hand, ALA safety in pregnant women and its pharmacokinetics by vaginal route, have to be studied in depth. Moreover, ALA efficacy has to be confirmed in a much larger sample of patients.

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.). This review will focus on the chemical structures, mechanism of action and main structure-activity relationships of anticonvulsant agents acting through glutamate neurotransmission.

Myo-inositol in a new pharmaceutical form: a step forward to a broader clinical use.

OBJECTIVE: Dose-dependent side effects related to myo-inositol (MI) oral administration represent a significant shortcoming for its clinical use. Aiming to search for a pharmaceutical form able to be better absorbed, the pharmacokinetic (PK) profile of the new manufactured MI soft gelatin capsule form was evaluated and compared with the commercially available MI powder. RESEARCH DESIGN AND METHODS: A single-dose relative trial, consisting of four phases, was performed on 20 healthy volunteers who received different doses of MI powder and MI soft gelatin capsules. PK profiles related to the two pharmaceutical forms were obtained by analysis of MI plasma concentration, and the respective MI bioavailability was compared. RESULTS: The administration of MI powder and MI soft gelatin capsules resulted in a different bioavailability. MI soft gelatin capsule form showed similar PK parameters compared with three times higher doses of MI in powder form. CONCLUSIONS: MI soft gelatin capsules displayed an improved bioavailability, allowing to substantially reduce the administered dose and to minimize the dose-dependent side effects. Considering the number of conditions in which MI supplementation is recommended, this evidence could support a broader use of MI in clinical practice.

Myo-inositol soft gel capsules may prevent the risk of coffee-induced neural tube defects.

OBJECTIVE: Neural tube defects (NTDs) are classified as folate sensitive (about 70%) and folate resistant (about 30%); although folic acid is able to prevent the former, several data have shown that inositol may prevent the latter. It has recently been proposed that coffee intake might represent a risk factor for NTD, likely by interfering with the inositol signaling. In the present study, we tested the hypothesis that, beside affecting the inositol signaling pathway, coffee also interferes with inositol absorption. RESEARCH DESIGN AND METHODS: In order to evaluate coffee possible negative effects on inositol gastrointestinal absorption, a single-dose bioavailability trial was conducted. Pharmacokinetics (PK) parameters of myo-inositol (MI) powder and MI soft gelatin capsules swallowed with water and with a single 'espresso' were compared. PK profiles were obtained by analysis of MI plasma concentration, and the respective MI bioavailability was compared. RESULTS: Myo-inositol powder administration was negatively affected by coffee intake, thus suggesting an additional explanation to the interference between inositol deficiency and coffee consumption. On the contrary, the concomitant single 'espresso' consumption did not affect MI absorption following MI soft gelatin capsules administration. Furthermore, it was observed that MI soft gelatin capsule administration resulted in improved bioavailability compared to the MI powder form. CONCLUSIONS: Myo-inositol soft gelatin capsules should be considered for the preventive treatment of NTDs in folate-resistant subjects due to their higher bioavailability and to the capability to reduce espresso interference.

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. The demonstrated importance of the association between IN and LEDGF/p75 in HIV-1 integration suggests the possibility that this protein-protein interaction (PPI) could be exploited as an antiviral target. We describe herein the progress to date in developing inhibitors of this promising target.

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. On these bases, we have concentrated our research on the identification of small molecules able to inhibit two different stages of the integration process: the IN strand-transfer phase and the IN-LEDGF/p75 interaction. We found that the 4-[1-(4-fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (CHI-1043) is an interesting anti-HIV agent exhibiting dual inhibitory effects. This work has suggested the possibility of also constructing an integration dual inhibitor using a design-in strategy.

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). The binding mode of our molecules has been investigated using the recently published crystal structure of the complex of full-length integrase from the prototype foamy virus in complex with its cognate DNA (PFV-IN/DNA). The results highlighted the ability of derivative 8e to assume the same binding mode of MK-0518 and GS 9137.

Docking studies on a new human immunodeficiency virus integrase-Mg-DNA complex: phenyl ring exploration and synthesis of 1H-benzylindole derivatives through fluorine substitutions.

A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been built. It was used to study the binding mode of integrase strand transfer inhibitor 1 (CHI-1043) and other fluorine analogues. Molecular modeling results prompted us to synthesize the designed derivatives which showed potent enzymatic inhibition at nanomolar concentration, high antiviral activity, and low toxicity. Microwave assisted organic synthesis (MAOS) was employed in several steps of the synthetic pathway, thus reducing reaction times and improving yields.