Icilio Guareschi and his amazing "1897 reaction".

Organic chemistry honors Icilio Guareschi (1847-1918) with three eponymic reactions, the best known ones being the Guareschi synthesis of pyridones and the Guareschi-Lustgarten reaction. A third Guareschi reaction, the so-called "Guareschi 1897 reaction", is one of the most unusual reactions in organic chemistry, involving the radical-mediated paradoxical aerobic generation of hydrocarbons in near-neutral water solution. A discussion of the mechanism of this amazing reaction, the only metal-free process that generates hydrocarbons, and the implications of the approach in biology and geosciences mirrors the multifaceted scientific personality of the discoverer.

Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis.

In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets.

Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders.

Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis.

A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies.

Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC values in the enzyme-based assay.

Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs.

Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions.

The Guareschi Pyridine Scaffold as a Valuable Platform for the Identification of Selective PI3K Inhibitors.

A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl-3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed.

Design, synthesis, and biological evaluation of combretabenzodiazepines: a novel class of anti-tubulin agents.

In the present manuscript, starting from the 1,4-benzodiazepin-2-one nucleus, a privileged structure in medicinal chemistry, we have synthesized a novel class of cis-locked combretastatins named combreatabenzodiazepines. They show similar cytotoxic and antitubulin activity compared to combretastatin A-4 in neuroblastoma cells, showing a better pharmacokinetic profile. This class of compounds has therefore the potential for further development as antitubulin agents.

Are 1,4- and 1,5-disubstituted 1,2,3-triazoles good pharmacophoric groups?

Over the last decade, 1,2,3-triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3-dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3-triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X-ray crystal structures of complexes between 1,2,3-triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole.

ZINClick: a database of 16 million novel, patentable, and readily synthesizable 1,4-disubstituted triazoles.

Since Professors Sharpless, Finn, and Kolb first introduced the concept of "click reactions" in 2001 as powerful tools in drug discovery, 1,4-disubstituted-1,2,3-triazoles have become important in medicinal chemistry due to the simultaneous discovery by Sharpless, Fokin, and Meldal of a perfect click 1,3-dipolar cycloaddition reaction between azides and alkynes catalyzed by copper salts. Because of their chemical features, these triazoles are proposed to be aggressive pharmacophores that participate in drug-receptor interactions while maintaining an excellent chemical and metabolic profile. Surprisingly, no virtual libraries of 1,4-disubstituted-1,2,3-triazoles have been generated for the systematic investigation of the click-chemical space.

A concise synthesis of pyrazole analogues of combretastatin A1 as potent anti-tubulin agents.

Combretastatin A1 (CA1) binds to the β-subunit at the colchicine binding site of tubulin and inhibits polymerization. As such, it is both an antitumor agent and a vascular disrupting agent. It has been shown to be at least tenfold more potent than combretastatin A4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive ortho-quinone species that are assumed to be directly cytotoxic in tumor cells.

Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus.

Chikungunya virus (CHIKV) is an Arbovirus that is transmitted to humans primarily by the mosquito species Aedes aegypti. Infection with this pathogen is often associated with fever, rash and arthralgia. Neither a vaccine nor an antiviral drug is available for the prevention or treatment of this disease.

De novo computer-aided design of novel antiviral agents.

Computer-aided drug design techniques have become an integral part of the drug discovery process. In particular, de novo methodologies can be useful to identify putative ligands for a specific target relying only on the structural information of the target itself. Here we discuss the basic de novo approaches available and their application in antiviral drug design.

Identification of a sirtuin 3 inhibitor that displays selectivity over sirtuin 1 and 2.

As part of an effort to identify novel selective modulators of sirtuins, we synthesized and tested several isosteres and constrained analogues of nicotinamide. Biological data suggest that compound 2 is selective for Sirt3 over Sirt1 and Sirt2.

The tubulin colchicine domain: a molecular modeling perspective.

Computational approaches have been increasingly applied to drug design over the past three decades and have already provided some useful results in the discovery of anticancer drugs. Given the increased availability of crystal structures in recent years, a growing number of molecular modeling studies on tubulin have been reported. Herein we present a brief overview of the role played by computational methods in anti-tubulin research, specifically in the context of colchicine binding agent research.

[Stress urinary incontinence treatment using Surgimesh® Sling, evolution on patient quality of life and sexual activity during 12 months follow-up].

Introduction: Evaluation of quality of life (QOL) and sexual activity after using sub-urethral Surgimesh® Sling for female stress urinary incontinence (SUI).

Methods: Study with a total duration of 12 months. One hundred and sixty-eight patients presenting a SUI underwent surgery for a Surgimesh® Sling implantation.

Groebke multicomponent reaction and subsequent nucleophilic aromatic substitution for a convenient synthesis of 3,8-diaminoimidazo[1,2-a]pyrazines as potential kinase inhibitors.

In a program aimed at discovering novel protein kinase inhibitors, a convenient synthesis of 3,8-diaminoimidazo[1,2-a]pyrazines has been developed exploiting the isocyanide-based multicomponent Blackburn reaction, followed by a nucleophilic aromatic substitution with ammonia or primary and secondary amines. The potential of the reported scaffold is strengthened by the inhibition of STAT5-dependent transcription displayed by four of the synthesized compounds.

Replacement of the double bond of antitubulin chalcones with triazoles and tetrazoles: Synthesis and biological evaluation.

In the chalcone scaffold, it is thought that the double bond is an important structural linker but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. In this letter, we have replaced this olefinic portion of chalcones with two metabolically stable and chemically inert heterocyclic rings, namely triazole or tetrazole.

Essential role of the p110beta subunit of phosphoinositide 3-OH kinase in male fertility.

Phosphoinositide 3-kinases (PI3K) are key molecular players in male fertility. However, the specific roles of different p110 PI3K catalytic subunits within the spermatogenic lineage have not been characterized so far. Herein, we report that male mice expressing a catalytically inactive p110beta develop testicular hypotrophy and impaired spermatogenesis, leading to a phenotype of oligo-azoospermia and defective fertility.

A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry.

The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 + 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues.

Synthesis, biological evaluation, and molecular docking of Ugi products containing a zinc-chelating moiety as novel inhibitors of histone deacetylases.

HDAC inhibitors show great promise for the treatment of cancer. As part of a broader effort to explore the SAR of HDAC inhibitors, synthesis, biological evaluation, and molecular docking of novel Ugi products containing a zinc-chelating moiety are presented. One compound shows improved inhibitory potencies compared to SAHA, demonstrating that hindered lipophilic residues grafted on the peptide scaffold of the alpha-aminoacylamides can be favorable in the interaction with the enzyme.

Solution-phase parallel synthesis and biological evaluation of combretatriazoles.

Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins containing a triazole ring (combretatriazoles). To achieve this, we have developed a column chromatography-free parallel solution-phase synthesis that exploits the reaction between azides and alpha-keto phosphorus ylids, which is known to regioselectively generate the 1,5-disubstituted triazoles.

Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage.

One of the great challenges of medicinal chemistry is to create novel, effective, chemotherapeutic agents that show specificity for cancer cells combined with low systemic toxicity. A novel idea is to target the enzymes of the NAD biosynthesis and recycling pathways given that cancer cells display a higher NAD turnover rate than healthy cells. To this end, the compound FK866 (APO866; (E)-N-[4-(1-benzoylpiperidin-4-yl) butyl]-3-(pyridin-3-yl) acrylamide), which blocks nicotinamide phosphoribosyltransferase (NMPRTase) has entered clinical trials as a potential chemotherapeutic agent.