Synthesis and biological evaluation of anti-Toxoplasma gondii activity of a novel scaffold of thiazolidinone derivatives

We designed and synthesised novel N-substituted 1,3-thiazolidin-4-one derivatives for the evaluation of their anti-Toxoplasma gondii efficacy. This scaffold was functionalised both at the N1-hydrazine portion with three structurally different moieties and at the lactam nitrogen with substituted benzyl groups selected on the basis of our previous structure-activity relationships studies. Using three different assay methods, the compounds were assessed in vitro to determine both the levels of efficacy against the tachyzoites of T. gondii (IC50 = 5-148 μM), as well as any evidence of cytotoxicity towards human host cells (TD50 = 68 to ≥320 μM). Results revealed that ferrocene-based thiazolidinones can possess potent anti-tachyzoite activity (TI =2-64)

Qualitative and quantitative phytochemical analysis of different extracts from Thymus algeriensis aerial parts

This study was performed to evaluate the metabolite recovery from different extraction methods applied to Thymus algeriensis aerial parts. A high-performance liquid chromatographic method using photodiode array detector with gradient elution has been developed and validated for the simultaneous estimation of different phenolic compounds in the extracts and in their corresponding purified fractions. The experimental results show that microwave-assisted aqueous extraction for 15 min at 100 C gave the most phenolics-enriched extract, reducing extraction time without degradation effects on bioactives. Sixteen compounds were identified in this extract, 11 phenolic compounds and five flavonoids, all known for their biological activities. Color analysis and determination of chlorophylls and carotenoids implemented the knowledge of the chemical profile of this plant

Atriplex mollis desf. Aerial parts: extraction procedures, secondary metabolites and color analysis

A method using high-performance liquid chromatography coupled with a photodiode array detector was proposed for the rapid characterization of different phenolic constituents from the extracts of Atriplex mollis aerial parts. Atriplex species are known for their multiple biological activities, but no information is available in the literature about A. mollis. With the aim to firstly characterize the main secondary metabolites of this plant, so as to orient better the biological evaluation, we applied three different extraction procedures and compared the chromatographic results. Microwave-assisted extraction gave the best yield and recovery of important compounds such as gallic acid, catechin, chlorogenic acid, p-OH benzoic acid, rutin, sinapinic acid, t-ferulic acid, naringenin and benzoic acid. These constituents belong to three important chemical classes: phenolic acids, flavonoids and monoterpenes. Color evaluation and analysis of chlorophylls (a and b) and carotenoids complete the preliminary profile of this plant. From these analyses, Atriplex mollis is a source of bioactive compounds (especially rutin, t-ferulic acid and gallic acid) and could be recommended as a plant of phyto-pharmaceutical relevance, opening new perspectives on this salt-tolerant plant

Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study

Periodontitis is an inflammatory disease caused by anaerobic bacteria, including Porphyromonas gingivalis. Lipopolysaccharide (LPS)-stimulated persistent inflammation is responsible for an increase in matrix metalloproteinase (MMP) expression, resulting in periodontal tissue destruction. The aim of the present study was to investigate synthesized bisphosphonic MMP inhibitors, in an in vitro model consisting of human gingival fibroblasts exposed to LPS, and to compare the biological responses to those induced by zoledronate (ZA), a commercial bisphosphonate. MTT and lactate dehydrogenase (LDH) assays were used to measure cell viability and cytotoxicity, respectively. ELISA was performed to evaluate prostaglandin E2 (PGE2), interleukin (IL)6 and collagen secretion, while western blotting was used to analyze MMP expression. No effect on viability and low cytotoxicity were observed following treatment with bisphosphonate compounds. In the present study, treatment with compound 1 did not increase the release of PGE2and IL6. Increased levels of collagen I secretion were reported when compound 3 and ZA were administered. An increase of MMP8 was observed following ZA treatment, while a decrease of MMP9 and MMP14 following treatment with compounds 1, 2 and ZA were reported. The performance of compound 1 was optimal in terms of cell viability. Compound 1 also did not induce inflammation, and had the ability to counteract LPS-induced increases in MMP expression. These data suggested that compound 1 was the most suitable treatment to progress to an in vivo animal study, with the aim to confirm its use for the treatment of periodontitis

In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover

Bisphosphonates (BPs) are well known clinically used drugs, commonly applied to treat osteoclast-mediated bone resorption. Some clinically used BPs were demonstrated to be able to inhibit the activity of matrix metalloproteinases (MMPs) (1), a protease family required to fully degrade all the components of the extracellular matrix during connective tissue remodelling (2). Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present work is to compare the effects on cell adhesion, cytotoxicity, inflammatory response occurrence and matrix turnover process in an in vitro model of primary human gingival fibroblasts (HGFs) treated with newly synthesized sulfonamide BPs and with zoledronic acid (ZA), a clinically used drug. Western blot was used to measure Procollagen I, β1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability, LDH was performed for toxicity evaluation, ELISA for Prostaglandin E2 (PGE2) secretion assessment. When compared with ZA, the treatment with the newly synthetized compounds shows increasing viability, Procollagen I expression and decreased expression of β1 integrin in HGFs. Higher levels of released LDH, PGE2 and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthetized compounds-treated samples.These findings imply that new BPs could accelerate the physiological matrix turnover, they are more able to preserve the soft tissue surrounding bone as they have neither inflammatory effects nor toxicity, along with reduced effects on the cell viability, which are instead typical side effects of ZA administration. We can conclude that the newly synthesized compounds are better tolerated, leading to the hypothesis that their use leads to connective tissues side effects reduction compared to clinically used drugs, even though several studies are required to deeply investigate the signaling cascades involved in the mechanism of action of these new BPs

Phosphonate Emerging Zinc Binding Group in Matrix Metalloproteinase Inhibitors

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, capable to degrade the extracellular matrix (ECM) in physiologic conditions. Because of their overexpression and pivotal role in many pathological events, they have been proposed as a therapeutic and prognostic target for a number of diseases. Selectivity among MMPs is essential for realizing the clinical potential of inhibitors. The design of MMP inhibitors (MMPIs) has largely focused on development of various compounds containing a zinc binding group (ZBG) in their structure, with hydroxamate being the most potent one. Due to the high degree of homology in the catalytic domain of all the MMPs, the specificity and selectivity of first generation hydroxamate MMPIs were minimal, with several off-target effects and binding to other metzincins. This review highlights the role of phosphonate as ZBG in the design and development of new MMPIs

The Compounds Responsible for the Sensory Profile in Monovarietal Virgin Olive Oils

Monovarietal virgin olive oils (VOOs) are very effective to study relationships among sensory attributes, the compounds responsible for flavour, and factors affecting them. The stimulation of the human sensory receptors by volatile and non-volatile compounds present in monovarietal virgin olive oils gives rise to the sensory attributes that describe their peculiar delicate and fragrant flavours. The formation of these compounds is briefly illustrated and the influence of the agronomic and technological factors that affect their concentrations in the oil is examined. The relationships between compounds responsible for the olive oil flavour and sensory attributes are discussed. Several approaches for the varietal differentiation of monovarietal virgin olive oils are also overviewed

Kinetics and Energetics of Thermal Cis-Trans Isomerization of a Resonance-Activated Azobenzene in BMIM-Based Ionic Liquids for PF6−/Tf2N− Comparison

BMIM PF6 (1-butyl-3-methylimidazolium hexafluorophosphate) and BMIM Tf2N (1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) are two conventional room-temperature ionic liquids widely employed and investigated as reaction media. Despite the presence of the same imidazolium ring in their structure they are different in many chemical and physical properties due to the nature of the anions. The thermal cis-trans isomerization of an electronically activated azobenzene have been used as reaction model to compare the behavior of PF6− and Tf2N−. Rotation is the mechanism by which the investigated azobenzene is converted into the trans isomer spontaneously in the dark both in BMIM PF6 and in BMIM Tf2N. The kinetic rate constants of the process have been determined at different temperatures and the activation energies of the reaction have been calculated according to the Arrhenius and Eyring equations. The results presented herein highlight different solute-solvent interactions involving the PF6− and Tf2N− anions during the cis-trans isomerization

Novel therapies for glaucoma: a patent review (2013-2019)

Introduction: Glaucoma is one of the main leading causes of irreversible blindness in the world. The treatment of this disease relies on the use of drugs able to reduce/control the intraocular pressure (IOP), one of the main risk factors for glaucoma. Current therapies are based on the use of compounds belonging to well-established categories (prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and cholinergic agonists). However, even if they are effective in reducing IOP, important side effects impair patient compliance, accounting for the necessity of novel therapy approaches. Therefore, new targets are emerging as alternative and more complete routes to fight glaucoma disease. Areas covered: This review provides a comprehensive update on the development state of innovative strategies against glaucoma describing results, administration routes, pharmaceutical compositions, structures, and SARs as well as the related shortcomings within the 2013-2019 range. Expert opinion: New innovative pharmacological targets have been explored in the last six years, allowing a broader therapeutic arsenal against glaucoma and IOP-related pathologies. The endocannabinoid system and FAAH inhibitors were the most investigated from a medicinal chemistry point of view

Inhibition of bacterial and human zincmetalloproteases by bisphosphonate- and catechol-containing compounds

Compounds containg catechol or bisphosphonate were tested as inhibitors of the zinc metalloproteases, thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) which are bacterial virulence factors, and the human matrix metalloproteases MMP-9 and −14. Inhibition of virulence is a putative strategy in the development of antibacterial drugs, but the inhibitors should not interfere with human enzymes. Docking indicated that the inhibitors bound MMP-9 and MMP-14 with the phenyl, biphenyl, chlorophenyl, nitrophenyl or methoxyphenyl ringsystem in the S1′-subpocket, while these ringsystems entered the S2′- or S1 -subpockets or a region involving amino acids in the S1′- and S2′-subpockets of the bacterial enzymes. An arginine conserved among the bacterial enzymes seemed to hinder entrance deeply into the S1′-subpocket. Only the bisphosphonate containing compound RC2 bound stronger to PLN and TLN than to MMP-9 and MMP-14. Docking indicated that the reason was that the conserved arginine (R203 in TLN and R198 in PLN) interacts with phosphate groups of RC2