Davide Garella

Phytotherapeutics: an evaluation of the potential of 1000 plants

Objective:  The aim of this review is to evaluate and summarize the available scientific information on the commonest plant extracts marketed in Western countries. In view of the intense, ongoing search for new plant extracts with powerful anti‐inflammatory activity, we paid particular attention to this topic. The aim is to provide broad coverage of as many potentially useful plants as possible and then to focus on those with the greatest therapeutic potential.

Ultrasound-Promoted Copper-Catalyzed Azide-Alkyne Cycloaddition

†Dipartimento di Scienza e Tecnologia del Farmaco, Universita di Torino, Via Giuria 9, 10125Torino, Italy, and Department of Chemistry, The Scripps Research Institute, 10550 North TorreyPines Road, La Jolla, California 92037The 1,3-dipolar cycloaddition reaction of azides and alkynes has been known for over 100years and was studied extensively by Huisgen and co-workers in the 1960s.

Microwave-assisted synthesis of N-heterocycles in medicinal chemistry

The syntheses of almost all N-heterocycles have now been successfully performed under microwave irradiation and have provided significant improvements in the reaction time and efficiency. The peculiar properties of dielectric heating give it the ability to strongly promote cyclocondensation, cycloaddition and selective N-heterocycle functionalisation and it has, therefore, very much caught the attention of the medicinal chemistry community. In this work, we present an overview of recent literature and technical advances in this research field with the aim of providing insight into the applications of microwave-assisted synthesis in the preparation of the main drug categories that contain N-heterocycle scaffolds.

Rapid purification/oxidation of multi-walled carbon nanotubes under 300 kHz-ultrasound and microwave irradiation

The use of ultrasound (US) and microwaves (MW) in the oxidation and purification of multi-walled carbon nanotubes (MWCNTs) was investigated. These techniques, in particular US at a frequency of 300 kHz, strongly accelerate the process and avoid the heavy structural damage, observed at the 20–35 kHz classic range, even at low power. Due to the residual metal catalyst on the head of MWCNTs, MW heating is strongly absorbed, causing the rupture of the tip and the loss of the metal. All our chemico-physical treatment types were performed by suspending the CNTs in a 3 ∶ 1 H2SO4/HNO3 mixture. The resulting samples were investigated by TEM microscopy, TGA analyses and Raman spectroscopy, while the degree of oxidation was estimated by colourimetric analyses.

Fast, Solvent-Free, Microwave-Promoted Friedländer Annulation with a Reusable Solid Catalyst

A fast, solvent-free method is described for the synthesis of substituted quinoline derivatives via Friedländer cyclization, employing a reusable solid catalyst (silica-propylsulfonic acid). Although it worked best under microwave irradiation (with generally more than 90% isolated yields in 30 min), the reaction was also feasible under conventional heating (with fair to good yields in about 5 h).

Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis.

Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we describe the synthesis and chemical tuning of α,β-unsaturated electrophilic warheads toward the development of antipyroptotic compounds. Their pharmacological evaluation and structure-activity relationships are also described. Compound 9 was selected as a model of this series, and it proved to be a reactive Michael acceptor, irreversibly trapping thiol nucleophiles, which prevented both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner. Moreover, 9 and other structurally related compounds, inhibited caspase-1 and NLRP3 ATPase activities. Our findings can contribute to the development of covalent, multitarget antipyroptotic compounds targeting molecular components of the NLRP3 inflammasome regulatory pathway.

Suzuki cross-couplings of (hetero)aryl chlorides in the solid-state

The ultrasound-assisted cross-linking of chitosan with hexamethylene diisocyanate with the simultaneous incorporation of Pd(OAc)2 resulted in a catalyst which is suitable for the solid-state Suzuki cross-coupling of poorly reactive (hetero)aryl chlorides with phenylboronic acid. Reactions were carried out solvent-free in a planetary ball mill allowing the catalyst to be recycled several times.

Solvent-free chemoselective oxidation of thioethers and thiophenes by mechanical milling

Organosulphur compounds can be easily and selectively oxidized to sulfones using a small excess of Oxone(®) (1.6 eq.) under solventless mechanical milling conditions. This green procedure has been efficiently applied to a series of model compounds and to the desulphurization of medium/high sulphur content paraffins (up to 3000 mg kg(-1)).

Ultrasound-enhanced one-pot synthesis of 3-(Het)arylmethyl-4-hydroxycoumarins in water

3-(Aryl)methyl-4-hydroxycoumarins were produced in good to excellent yields by reaction between 4-hydroxycoumarin and (hetero)aromatic aldehydes in the presence of Hantzsch 1,4-dihydropyridine (HEH) which works as an hydride donor (i.e., in a sequential Knoevenagel-reductive Michael addition). The sonochemical-assisted procedure (method B) provides an improved and accelerated conversion when compared to conventional silent reactions (method A). Experiments carried out according to method B showed that the reaction could be more efficiently run in the absence of organic solvents, at 30-40°C in open vessel, without the need of an excess HEH and with simplified work-up and separation procedures.

Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors.

NLRP3 inflammasome plays a key role in the intracellular activation of caspase‐1, processing of pro‐inflammatory interleukin‐1β (IL‐1β), and pyroptotic cell death cascade. The overactivation of NLRP3 is implicated in the pathogenesis of autoinflammatory diseases, known as cryopyrin‐associated periodic syndromes (CAPS), and in the progression of several diseases, such as atherosclerosis, type‐2 diabetes, gout, and Alzheimers disease. In this study, the synthesis of acrylamide derivatives and their pharmaco‐toxicological evaluation as potential inhibitors of NLRP3‐dependent events was undertaken. Five hits were identified and evaluated for their efficiency in inhibiting IL‐1β release from different macrophage subtypes, including CAPS mutant macrophages. The most attractive hits were tested for their ability to inhibit NLRP3 ATPase activity on human recombinant NLRP3. This screening allowed the identification of 14, 2‐(2‐chlorobenzyl)‐N‐(4‐sulfamoylphenethyl)acrylamide, which was able to concentration‐dependently inhibit NLRP3 ATPase with an IC50 value of 74 μm. The putative binding pose of 14 in the ATPase domain of NLRP3 was also proposed.