This is a review of the chemistry, pharmacological and biomedical applications of bicyclic 5-6 systems possessing a five-membered ring with two heteroatoms fused onto a six-membered ring with one heteroatom. During the last decade the synthesis and transformations of these bicyclic 5-6 systems, especially that of imidazo-, pyrazolo-, oxazolo-, thiazolo- and isothiazolopyridines have received considerable attention due to their biological significance. This review covers theoretical and structural properties and recent methodologies, such as direct C-H-bond activation, multicomponent reactions, chemoselective transformations, as well as other new innovative approaches to provide molecules for the drug-like chemical space. The review is focused on medicinal chemistry application of these heterocyclic systems.

In inflammatory diseases, polymorphonuclear neutrophils (PMNs) are known to produce elevated levels of pro-inflammatory cytokines and proteases. To limit ensuing exacerbated cell responses and tissue damage, novel therapeutic agents are sought. 4aa and 4ba, two pyridazinone-scaffold-based phosphodiesterase-IV inhibitors are compared in vitro to zardaverine for their ability to: (1) modulate production of pro-inflammatory mediators, reactive oxygen species (ROS), and phagocytosis; (2) modulate degranulation by PMNs after transepithelial lung migration. Compound 4ba and zardaverine were tested in vivo for their ability to limit tissue recruitment of PMNs in a murine air pouch model. In vitro treatment of lipopolysaccharide-stimulated PMNs with compounds 4aa and 4ba inhibited the release of interleukin-8, tumor necrosis factor-α, and matrix metalloproteinase-9. PMNs phagocytic ability, but not ROS production, was reduced following treatment. Using a lung inflammation model, we proved that PMNs transmigration led to reduced expression of the CD16 phagocytic receptor, which was significantly blunted after treatment with compound 4ba or zardaverine. Using the murine air pouch model, LPS-induced PMNs recruitment was significantly decreased upon addition of compound 4ba or zardaverine. Our data suggest that new pyridazinone derivatives have therapeutic potential in inflammatory diseases by limiting tissue recruitment and activation of PMNs.

Osteosarcoma is a rare primary bone cancer that mostly affects children and young adults. Current therapeutic approaches consist of combining surgery and chemotherapy but remain unfortunately insufficient to avoid relapse and metastases. Progress in terms of patient survival has remained the same for 30 years. In this study, novel pyridazinone derivatives have been evaluated as potential anti-osteosarcoma therapeutics because of their anti-type 4 phosphodiesterase activity, which modulates the survival of several other cancer cells. By using five-four human and one murine osteosarcoma-cell lines, we demonstrated differential cytotoxic effects of four pyridazinone scaffold-based compounds (mitochondrial activity and DNA quantification). Proapoptotic (annexin V positive cells and caspase-3 activity), anti-proliferative (EdU integration) and anti-migratory effects (scratch test assay) were also observed. Owing to their cytotoxic activity in in vitro conditions and their ability to limit tumor growth in a murine orthotopic osteosarcoma model, our data suggest that these pyridazinone derivatives might be hit-candidates to develop new therapeutic strategies against osteosarcoma.

Designing nanoprobes in which quantum dots (QDs) are used as photoluminescent labels is an especially promising line of research due to their possible medical applications ranging from disease diagnosis to drug delivery. In spite of the significant progress made in designing such nanoprobes, the properties of their individual components, i.e., photoluminescent QDs, vectorization moieties, and pharmacological agents, still require further optimization to enhance the efficiency of diagnostic or therapeutic procedures. Here, we have developed a method of engineering compact multifunctional nanoprobes based on functional components with optimized properties: bright photoluminescence of CdSe/ZnS (core/shell) QDs, a compact and effective antitumor agent (an acridine derivative), and direct conjugation of the components via electrostatic interaction, which provides a final hydrodynamic diameter of nanoprobes smaller than 15 nm. Due to the possibility of conjugating various biomolecules with hydroxyl and carboxyl moieties to QDs, the method represents a versatile approach to the biomarker-recognizing molecule imaging of the delivery of the active substance as part of compact nanoprobes.

Cyclic nucleotide phosphodiesterase type 4 (PDE4), that controls intracellular level of cyclic nucleotide cAMP, has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases. Here we describe the development of two families of pyridazinone derivatives as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4,5-dihydropyridazinone representatives possess promising activity, selectivity towards PDE4 isoenzymes and are able to reduce IL-8 production by human primary polymorphonuclear cells.

Photoluminescent quantum dots (QDs) due to their unique optical properties and capacity for conjugation with biomolecules are widely used in biomedicine. However, numerous by-products of bioconjugation can seriously influence the interaction of these nanoprobes and their targets. The use of size exclusion chromatography (SEC) for the separation of QDs and by-products of bioconjugation is rather challenging because of the difference in chemical and physical nature of nanoparticles and biomolecules, which makes the choice of stationary phases for SEC a complicated task. Here we have investigated the efficiency of SEC purification of water-soluble CdSe/ZnS QDs and QD-based conjugates from polyethylene glycol derivatives serving as stabilizing ligands, as well as bis-netropsin and 4,5,9-trisubstituted acridine derivative serving as DNA ligands using Sephadex resins with different porosities. We have found that multiple SEC cycles using popular pre-packed Sephadex G25 columns does not provide efficient purification of QDs, whereas Sephadex G100 and G200 are much more efficient after a single SEC run because of the optimal peak resolution and allow preserving the colloidal stability of QDs. Our results show that the use of less common chromatographic media in the group of Sephadex resins allows efficient purification of QD bioconjugates from contaminants for their subsequent use in bioimaging or diagnostics.

Photoluminescent quantum dots (QDs), due to their unique optical properties and capacity for conjugation with biomolecules, are widely used in biomedicine. However, numerous byproducts of bioconjugation may seriously influence the interaction of these nanoprobes and their targets. The use of size exclusion chromatography (SEC) for the separation of QDs and byproducts of bioconjugation is rather challenging because of the difference in the chemical and physical nature of nanoparticles and biomolecules, which makes the choice of stationary phases for SEC a complicated task. Here we propose a detailed protocol for SEC purification of water-soluble CdSe/ZnS QDs and QD conjugates using Sephadex resins with different porosities and investigate the efficiency of SEC purification of these materials as exemplified by poly(ethylene glycol) derivatives serving as QD-stabilizing ligands, as well as two types of small biomolecules, bis-netropsin and 4,5,9-trisubstituted acridine. We demonstrate that even multiple SEC cycles using the popular prepacked Sephadex G25 columns do not provide efficient purification of QDs, whereas Sephadex G100 and G200 are much more efficient after a single SEC run because of the optimal peak resolution and preservation of the colloidal stability of QDs. Our results show that the use of less common chromatographic media in the group of Sephadex resins allows efficient purification of QD bioconjugates from contaminants for their subsequent use in bioimaging or diagnostics. The proposed SEC protocol can be adapted for purification of not only CdSe-based QDs but also other types of water-soluble nanocrystals with similar sizes and surface properties.

Sixteen 5-aryl-substituted isothiazol-3(2H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2H)-one-1-oxide or -1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N-tert-butylisothiazolone series, the 5-phenyl-substituted analog (la) excelled in the inhibition of tumor-associated hCA IX and XII (K-i=4.5 and K-i= 4.3 nM, respectively) with excellent selectivity against off target hCA I and II isoenzymes (S > 2222 and S> 2325, respectively). Since the highest inhibition activities were observed with N-tert-butyl derivatives, lacking a zinc-binding group, we suppose to have a new binding mode situated out of the active site. Additionally, three free-NH containing analogs (3a, 4a, 3i) have also been prepared in order to study the impact of free-NH containing N-acyl-sulfinamide- (-SO-NH-CO-) or N-acyl-sulfonamide-type (-SO2-NHCO-) derivatives on the inhibitory potency and selectivity. Screening experiments evidenced 5-phenylisothiazol-3(2H)-one-1,1-dioxide (4a), the closest saccharin analog, to be the most active derivative with inhibition constants of K-i = 40.3 nM and K-i= 9.6 nM against hCA IX and hCA XII, respectively. The promising biological results support the high potential of 5-arylisothiazolinone-1,(1)-(di)oxides to be exploited for the design of potent and cancer-selective carbonic anhydrase inhibitors. (C) 2019 Elsevier Masson SAS. All rights reserved.

Ces vingt-cinq dernieres annees ont vu emerger la possibilite d’une societe reposant sur un apport carbone biosource en remplacement du carbone fossile, transition souvent appelee a tort « societe decarbonee ». Le territoire champardennais, terre agricole, s’est engage des les annees 1990 dans une demarche de bioraffinerie durable en associant recherche academique et acteurs economiques et politiques. C’est dans ce contexte que s’est developpee une recherche en chimie du vegetal tournee vers les secteurs a moyenne ou haute valeur ajoutee en visant des produits de specialite ou des actifs originaux et performants dans des domaines aussi varies que les materiaux, la chimie fine, l’environnement, l’agrochimie, la sante ou la cosmetique.

• Synthesis of novel cyclodepsipeptide alkyl/arylsulfonylhydrazide based derivatives. • Compounds 5 and 8 exhibited the best activities towards HDAC-3. • A direct transposition of sulfonylhydrazide-type ZBG from MMPIs to HDACIs must be done cautiously. • Our results help for a better understanding of the structural effect of the ZBG on HDAC activity.

Outstanding Medchem in France: Guest editors Janos Sapi, Luc Van Hjfte, and Patrick Dallemagne look back at the 52nd International Conference on Medicinal Chemistry (RICT 2016) held in Caen, France. They discuss the history of the French Medicinal Chemistry Society (Société de Chimie Thérapeutique, SCT) and provide highlights of last year's events, including some key presentations now collected in this Special Issue.

The metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) is effectively inhibited by primary sulfonamides which coordinate as anions to the zinc ion from its active site. Inhibition of CAs has pharmacologic applications in the treatment of many diseases, but many sulfonamides are promiscuous inhibitors of most isoforms known to date, leading to side effects of these drugs. In a series of 4-aryl-benzenesulfonamides with effective inhibitory action against human (h) isoforms hCA I, II, IX and XII and selectivity for some of them, we demonstrate by means of X-ray crystallographic studies of enzyme-inhibitor adducts, that the tail present on the benzenesulfonamide scaffold significantly contributes to the observed inhibition/selectivity profile. This study may bring additional information for the structure-based drug design of effective/isoform-selective zinc-binding CA inhibitors.

The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the understanding of the roles of MMPs in different diseases. Most MMP probes designed are fluorogenic substrates, often suffering from photo- and chemical instability and providing a fluorescence signal of moderate intensity, which is difficult to detect and analyze when dealing with crude biological samples. Here, an inhibitor that inhibits MMP-2 more selectively than Galardin has been synthesized and used for enzyme labeling and detection of the MMP-2 activity. A complete MMP-2 recognition complex consisting of a biotinylated MMP inhibitor tagged with the streptavidin-quantum dot (QD) conjugate has been prepared. This recognition complex, which is characterized by a narrow fluorescence emission spectrum, long fluorescence lifetime, and negligible photobleaching, has been demonstrated to specifically detect MMP-2 in in vitro sandwich-type biochemical assays with sensitivities orders of magnitude higher than those of the existing gold standards employing organic dyes. The approach developed can be used for specific in vitro visualization and testing of MMP-2 in cells and tissues with sensitivities significantly exceeding those of the best existing fluorogenic techniques.

Benzenesulfonamides bearing various substituted (hetero)aryl rings in the para-position were prepared by palladium nanoparticle-catalyzed Suzuki-Miyaura cross-coupling reactions and evaluated as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors against isoforms hCA I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition against hCA I isoform, whereas the other cytosolic isoenzyme, hCA II, was strongly affected. The major part of these new derivatives acted as potent inhibitors of the tumor-associated isoform hCA XII. An opposite trend was observed for phenyl, naphthyl, and various heteroaryl substituted benzenesulfonamides which displayed subnanomolar hCA IX inhibition while poorly inhibiting the other tumor-associated isoform hCA XII. The inhibition potency and influence of the partially restricted aryl-aryl bond rotation on the activity/selectivity were rationalized by means of X-ray crystallography of the adducts of hCA II with several 4-arylbenzenesulfonamides.

Over the decades the Smiles rearrangement and its variants have become essential synthetic tools in modern synthetic organic chemistry. In this mini-review we summarized some very recent results of the radical version of these rearrangements. The selected examples illustrate the synthetic power of this approach, especially if it is incorporated into a domino process, for the preparation of polyfunctionalized complex molecules.

Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease‐implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer‐associated isoforms and reduce side effects. Four benzenesulfonamide‐based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active‐site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active‐site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.

The mechanism of the TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole was studied by a combination of theoretical and experimental techniques. The energy profile of plausible reaction paths was evaluated by DFT calculations, and various reaction intermediates were isolated or observed in solution by NMR spectroscopy. Theoretical and experimental results indicate that the reaction proceeds in three steps, all promoted by titanium: (1) formation of the enolate ion of methyl acetoacetate, (2) Knoevenagel condensation of the enolate ion and aldehyde, and (3) Michael addition of indole to the Knoevenagel adduct. The study sheds light on the role of titanium in the reaction, providing a mechanistic model for analogous reactions.