Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: Part 2. Synthesis of rigid pyrazolones

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity

Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure–activity relationship analysis

Antiherpevirus activity of Artemisia arborescens essential oil and inhibition of lateral diffusion in Vero cells

<p>Abstract</p> <p>Background</p> <p>New prophylactic and therapeutic tools are needed for the treatment of herpes simplex virus infections. Several essential oils have shown to possess antiviral activity <it>in vitro </it>against a wide spectrum of viruses.</p> <p>Aim</p> <p>The present study was assess to investigate the activities of the essential oil obtained from leaves of <it>Artemisia arborescens </it>against HSV-1 and HSV-2</p> <p>Methods</p> <p>The cytotoxicity in Vero cells was evaluated by the MTT reduction method. The IC₅₀values were determined by plaque reduction assay. In order to characterize the mechanism of action, yield reduction assay, inhibition of plaque development assay, attachment assay, penetration assay and post-attachment virus neutralization assay were also performed.</p> <p>Results</p> <p>The IC₅₀values, determined by plaque reduction assay, were 2.4 and 4.1 μg/ml for HSV-1 and HSV-2, respectively, while the cytotoxicity assay against Vero cells, as determined by the MTT reduction method, showed a CC₅₀value of 132 μg/ml, indicating a CC₅₀/IC₅₀ratio of 55 for HSV-1 and 32.2 for HSV-2. The antiviral activity of <it>A. arborescens </it>essential oil is principally due to direct virucidal effects. A poor activity determined by yield reduction assay was observed against HSV-1 at higher concentrations when added to cultures of infected cells. No inhibition was observed by attachment assay, penetration assay and post-attachment virus neutralization assay. Furthermore, inhibition of plaque development assay showed that <it>A. arborescens </it>essential oil inhibits the lateral diffusion of both HSV-1 and HSV-2.</p> <p>Conclusion</p> <p>This study demonstrates the antiviral activity of the essential oil <it>in toto </it>obtained from <it>A. arborescens </it>against HSV-1 and HSV-2. The mode of action of the essential oil as antiherpesvirus agent seems to be particularly interesting in consideration of its ability to inactivate the virus and to inhibit the cell-to-cell virus diffusion.</p

Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: preliminary data and computational analysis

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 \u3bcg/mL (0.37-0.75 \u3bcM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans

TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione

Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS

Saggi e dosaggi microbiologici della Farmacopea

Scritto da un gran numero di Docenti titolari delle cattedre di Microbiologia nelle Facoltà di Farmacia degli Atenei Italiani, questo testo è specifico per gli studenti di Farmacia in quanto offre una visione farmaceutica della Microbiologia proponendo le nozioni di base della Microbiologia ad indirizzo sanitario e sviluppando allo stesso tempo argomenti più vicini alla figura del Farmacista, come gli aspetti legati al farmaco antibiotico, alla produzione farmaceutica, ai Saggi e Dosaggi della Farmacopea. Il testo è suddiviso in due sezioni - Microbiologia generale e Microbiologia speciale - ciascuna suddivisa in capitoli articolati in nozioni facile e snelle, ricchi dal punto di vista iconografico, cui si aggiungono vari approfondimenti su argomenti specifici o di attualità. Punti di forza Il testo presenta tutti gli argomenti base della microbiologia ad indirizzo sanitario in maniera snella e facilmente comprensibile in modo da adattarsi ai vari tipi di corsi in cui l'esame in questione è previsto in anni diversi e quindi affrontato con una preparazione differente. Destinatari Facoltà di Farmacia - idoneo sia per i corsi quinquennali (Laurea Magistrale in Farmacia e Laurea in Chimica e Tecnologie Farmaceutiche) che per i corsi triennali (Erboristeria e Informatore Scientifico, etc.)