A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties, by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the blood-brain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated

Antiviral Peptides as Anti-Influenza Agents

Influenza viruses represent a leading cause of high morbidity and mortality worldwide. Approaches for fighting flu are seasonal vaccines and some antiviral drugs. The development of the seasonal flu vaccine requires a great deal of effort, as careful studies are needed to select the strains to be included in each year’s vaccine. Antiviral drugs available against Influenza virus infections have certain limitations due to the increased resistance rate and negative side effects. The highly mutative nature of these viruses leads to the emergence of new antigenic variants, against which the urgent development of new approaches for antiviral therapy is needed. Among these approaches, one of the emerging new fields of “peptide-based therapies” against Influenza viruses is being explored and looks promising. This review describes the recent findings on the antiviral activity, mechanism of action and therapeutic capability of antiviral peptides that bind HA, NA, PB1, and M2 as a means of countering Influenza virus infection

Geometric Isomerism of an Acetamidino Derivative Determined by NMR Investigations

Amidines, the nitrogen analogues of carboxylic acids, show interesting roles as pharmacophore groups in biologically active agents and in compounds of pharmaceutical interest. In the last years, our research group disclosed inhibitors of inducible and neuronal Nitric Oxide Synthase (iNOS and nNOS, respectively) containing the amidino moiety, with the aim to extend the study of the possible ligand-enzyme interactions. Here we discuss the synthesis and spectral studies of acetamidino derivative N-(2-(pyrrolidin-1-yl)ethyl)acetimidamidinium bromide, and how these studies led us to identification of a E/Z configurational change, which could be helpful in elucidating the ligand-enzyme interactions

Design, synthesis and biological evaluation of imidazole and triazole-based carbamates as novel aromatase inhibitors

In the search for novel aromatase inhibitors, a series of triazole and imidazole-based carbamate derivatives were designed and synthesized. Final compounds were thus evaluated against human aromatase by in vitro kinetic experiments in a fluorimetric assay in comparison with letrozole. The effect of most active derivatives 13a and 15c was then evaluated in vitro on the human breast cancer cell line MCF7 by MTT assay, cytotoxicity assay (LDH release) and cell cycle analysis, revealing a dose-dependent inhibition profile of cell viability and low micromolar IC50 values. In addition, docking simulations were also carried out to elucidate at a molecular level of detail the binding modes adopted to target human aromatase

Druggability profile of stilbene-derived PPAR agonists: Determination of physicochemical properties and PAMPA study

PPAR agonists represent a new therapeutic opportunity for the prevention and treatment of neurodegenerative disorders, but their pharmacological success depends on favourable pharmacokinetic properties and capability to cross the BBB. In this study, we assayed some PPAR agonists previously synthesized by us for their physicochemical properties, with particular references to lipophilicity, solubility and permeability profiles, using the PAMPA. Although tested compounds showed high lipophilicity and low aqueous solubility, the results revealed a good overall druggability profile, encouraging further studies in the field of neurodegenerative diseases

Design, synthesis and biological evaluation of aromatase inhibitors based on sulfonates and sulfonamides of resveratrol

A library of sulfonate and sulfonamide derivatives of Resveratrol was synthesized and tested for its aromatase inhibitory potential. Interestingly, sulfonate derivatives were found to be more active than sulfonamide bioisosteres with IC50 values in the low micromolar range. The sulfonate analogues 1b–c and 1j exhibited good in vitro antiproliferative activity on the MCF7 cell line, evidenced by MTT and LDH release assays. Structure–activity relationships suggested that electronic and lipophilic properties could have a different role in promoting the biological response for sulfonates and sulfonamides, respectively. Docking studies disclosed the main interactions at a molecular level of detail behind the observed inhibition of the more active compounds whose chemical stability has been evaluated with nano-liquid chromatography. Finally, 1b–c and 1j were highlighted as sulfonates to be further developed as novel and original aromatase inhibitors

Benzenesulfonamide derivatives as Vibrio cholerae carbonic anhydrases inhibitors: a computational-aided insight in the structural rigidity-activity relationships

Vibrio cholerae causes life-threatening infections in low-income countries due to the rise of antibacterial resistance. Innovative pharmacological targets have been investigated and carbonic anhydrases (CAs, EC: 4.2.1.1) encoded by V. cholerae (VchCAs) emerged as a valuable option. Recently, we developed a large library of para- and meta-benzenesulfonamides characterised by moieties with a different flexibility degree as CAs inhibitors. Stopped flow-based enzymatic assays showed strong inhibition of VchαCA for this library, while lower affinity was detected against the other isoforms. In particular, cyclic urea 9c emerged for a nanomolar inhibition of VchαCA (KI = 4.7 nM) and high selectivity with respect to human isoenzymes (SI≥ 90). Computational studies revealed the influence of moiety flexibility on inhibitory activity and isoform selectivity and allowed accurate SARs. However, although VchCAs are involved in the bacterium virulence and not in its survival, we evaluated the antibacterial activity of such compounds, resulting in no direct activity