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synthesis of a pyrazole containing compound was achieved by reacting phenyl hydrazine with (E)-2-((4-bromophenyl) diazinyl)-1-phenylbutane-1,3-dione to produce 4-((4-bromophenyl) diazinyl)-5-methyl-1,3-diphenyl-pyrazole and characterization using mass spectrometer, 1 H NMR and 13 C NMR. The pharmacological evaluation of the synthesized compound, denoted as (KA5), against Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 29213 and Clostridiums sporogeneses ATCC 19404, indicate that there is no promising antibacterial activity. However, KA5 shows a competitive anticancer activity (IC 50 : 8.5μM) upon its evaluation against hepatocellular carcinoma cell line (HepG 2) compared to sorafenib (IC 50 : 4.51μM). Moreover, human skin fibroblast (HSF) was used to investigate the effect of KA5 on normal cell lines, (IC 50 : 5.53μM). The presented biological evaluations resulted in better understanding of structure-activity relationship for 1, 3, 4-trisubstituted pyrazoles and revealed a great opportunity for more investigations for novel pyrazole-containing anticancer agents.

Introduction: This study focuses on the development of novel antimicrobial agents. A Schiff base ligand, 6-(2-(4-hydroxy-3-methoxybenzylideneamino)-2-(4-hydroxyphenyl)acetamido)-3,3-dimethyl-7-oxo- 4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, synthesized through the condensation of amoxicillin and vanillin in methanol, served as the foundation. Polydentate mixed ligand complexes were then formed by reacting the Schiff base with metal ions (Fe(II), Co(II), Ni(II), Cu(II), and Zn(II)) and nicotinamide in specific ratios., Methods: Characterization involved various techniques, such as 1 H-NMR, FT-IR, UV-Vis, and elemental analysis for the ligand, and Atomic Absorption, FT-IR, UV-Vis, magnetic susceptibility, and conductance measurements for the Schiff base-metal ion complexes., Results: Quantum chemical features of both ligands and metal complexes were computed, refining their electronic and molecular structures theoretically. Antimicrobial activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, Acinetobacter baumannii , and Pseudomonas aeruginosa was assessed for the starting materials, ligands, and synthesized complexes, revealing significant effects on certain species. In-silico binding modes with Escherichia coli (PDB ID: 5iq9) were determined through molecular docking., Conclusion: This study underscores the potential applications of the Schiff base ligands and their metal complexes in developing new antimicrobial agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nicotinamide riboside chloride (NRCl) is an effective form of vitamin B3. However, it cannot be used in ready-to-drink (RTD) beverages or high-water activity foods because of its intrinsic instability in water. To address this issue, we synthesized nicotinamide riboside trioleate chloride (NRTOCl) as a new hydrophobic nicotinamide riboside (NR) derivative. Contrary to NRCl, NRTOCl is soluble in an oil phase. The results of stability studies showed that NRTOCl was much more stable than NRCl both in water and in oil-in-water emulsions at 25 °C and 35 °C. Finally, we evaluated the bioavailability of NRTOCl by studying its digestibility in simulated intestinal fluid. The results demonstrated that NRTOCl was partially digestible and released NR in the presence of porcine pancreatin in a simulated intestinal fluid. This study showed that NRTOCl has the potential to be used as an NR derivative in ready-to-drink (RTD) beverages and other foods and supplement applications.

It has recently been demonstrated that the rat poison vacor interferes with mammalian NAD metabolism, because it acts as a nicotinamide analog and is converted by enzymes of the NAD salvage pathway. Thereby, vacor is transformed into the NAD analog vacor adenine dinucleotide (VAD), a molecule that causes cell toxicity. Therefore, vacor may potentially be exploited to kill cancer cells. In this study, we have developed efficient enzymatic and chemical procedures to produce vacor analogs of NAD and nicotinamide riboside (NR). VAD was readily generated by a base-exchange reaction, replacing the nicotinamide moiety of NAD by vacor, catalyzed by Aplysia californica ADP ribosyl cyclase. Additionally, we present the chemical synthesis of the nucleoside version of vacor, vacor riboside (VR). Similar to the physiological NAD precursor, NR, VR was converted to the corresponding mononucleotide (VMN) by nicotinamide riboside kinases (NRKs). This conversion is quantitative and very efficient. Consequently, phosphorylation of VR by NRKs represents a valuable alternative to produce the vacor analog of NMN, compared to its generation from vacor by nicotinamide phosphoribosyltransferase (NamPT).

Two newly synthesized nicotinohydrazones, 6-bromo-2'-(2-chlorobenzylidene)nicotinohydrazide (1) and 6-bromo-2'-(3-bromo-5-chloro-2-hydroxybenzylidene)nicotinohydrazide methanol solvate (2), have been obtained and structurally characterized by spectroscopic method and single crystal X-ray determination. The molecules in both compounds are in E configuration regarding to the azomethine groups. The molecules of compound 1 are linked via hydrogen bonds of N?H∙∙∙O, generating one dimensional chains running along the c-axis direction. The hydrazone molecules of compound 2 are linked by methanol molecules via hydrogen bonds of N?H∙∙∙O and O?H∙∙∙N, generating dimers. The in vitro antimicrobial activities of these compounds indicate that they are interesting antibacterial agents.

Despite the availability of numerous routes to substituted nicotinates based on the Bohlmann-Rahtz pyridine synthesis, the existing methods have several limitations, such as the inevitable ortho-substitutions and the inability to conjugate vitamin B 3 to other pharmaceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B 3 ) from tryptophan, we herein report the development of a strategy for the synthesis of meta-aminoaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted meta-aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C-N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to ortho-unsubstituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester-substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research.

Currently, signal amplification by reversible exchange (SABRE) using para -hydrogen is an attractive method of hyperpolarization for overcoming the sensitivity problems of nuclear magnetic resonance (NMR) spectroscopy. Additionally, SABRE, using the spin order of para -hydrogen, can be applied in reaction monitoring processes for organic chemistry reactions where a small amount of reactant exists. The organic reaction monitoring system created by integrating SABRE and benchtop NMR is the ideal combination for monitoring a reaction and identifying the small amounts of materials in the middle of the reaction. We used a laboratory-built setup, prepared materials by synthesis, and showed that the products obtained by esterification of glycine were also active in SABRE. The products, which were synthesized esterified glycine with nicotinoyl chloride hydrochloride, were observed with a reaction monitoring system. The maximum SABRE enhancement among them (approximately 147-fold) validated the use of this method. This study is the first example of the monitoring of this organic reaction by SABRE and benchtop NMR. It will open new possibilities for applying this system to many other organic reactions and also provide more fruitful future applications such as drug discovery and mechanism study.

Background: The aim of the study was to compare widely used ordered subset expectation maximisation (OSEM) algorithm with a new Bayesian penalised likelihood (BPL) Q.Clear algorithm in 18F-PSMA-1007 PET/CT., Methods: We retrospectively assessed 25 18F-PSMA-1007 PET/CT scans with both OSEM and Q.Clear reconstructions available. Each scan was independently reported by two physicians both in OSEM and Q.Clear. SUVmax, SUVmean and tumour-to-background ratio (TBR) of each lesion were measured. Reports were also compared for their final conclusions and the number and localisation of lesions., Results: In both reconstructions the same 87 lesions were reported. Mean SUVmax, SUVmean and TBR were higher for Q.Clear than OSEM (7.01 vs 6.53 [p = 0.052], 4.16 vs 3.84 [p = 0.036] and 20.2 vs 16.8 [p < 0.00001], respectively). Small lesions (< 10 mm) had statistically significant higher SUVmax, SUVmean and TBR in Q.Clear than OSEM (5.37 vs 4.79 [p = 0.032], 3.08 vs 2.70 [p = 0.04] and 15.5 vs 12.5 [p = 0.00214], respectively). For lesions ≥ 10 mm, no significant differences were observed. Findings with higher tracer avidity (SUVmax ≥ 5) tended to have higher SUVmax, SUVmean and TBR values in Q.Clear (11.6 vs 10.3 [p = 0.00278], 7.0 vs 6.7 [p = 0.077] and 33.9 vs 26.7 [p < 0.00001, respectively). Mean background uptake did not differ significantly between Q.Clear and OSEM (0.42 vs 0.39, p = 0.07)., Conclusions: In 18F-PSMA-1007 PET/CT, Q.Clear SUVs and TBR tend to be higher (regardless of lesion localisation), especially for small and highly avid lesions. Increase in SUVs is also higher for lesions with high tracer uptake. Still, Q.Clear does not affect 18F-PSMA-1007 PET/CT specificity and sensitivity.

In our previous study, we reported a series of N-phenylisonicotinamide derivatives as novel xanthine oxidase (XO) inhibitors and identified N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (compound 1) as the most potent one with an IC 50 value of 0.312 μM. To further optimize the structure and improve the potency, a structure-based drug design (SBDD) strategy was performed to construct the missing H-bond between the small molecule and the Asn768 residue of XO. We introduced a tetrazole moiety at the 3'-position of the phenyl to serve as an H-bond acceptor and obtained a series of N-(3-(1H-tetrazol-1-yl)phenyl)isonicotinamide derivatives (2a-t and 6-8). Besides, to investigate the influence of the amide-reversal, some N-(pyridin-4-yl)-3-(1H-tetrazol-1-yl)benzamide derivatives (3c, 3e, 3i, 3k and 3u) were also synthesized and evaluated. Biological evaluation and structure-activity relationship analysis demonstrated that the 3'-(1H-tetrazol-1-yl) moiety was an excellent fragment for the N-phenylisonicotinamide scaffold; a substituted benzyloxy, especially, an m-cyanobenzyloxy (e.g., 2s), linking at the 4'-position was welcome for the potency; and the amide-reversal could damage the potency, so maintenance of the N-phenylisonicotinamide scaffold was essential. In summary, starting from compound 1, the SBDD effort successfully identified a promising XO inhibitor 2s (IC 50  = 0.031 μM), with a 10-fold gain in potency. Its potency was very close to the positive control topiroxostat (IC 50  = 0.021 μM). A Lineweaver-Burk plot indicated that compound 2s acted as a mixed-type XO inhibitor. Molecular docking and molecular dynamics simulations revealed that the tetrazole moiety could occupy the Asn768-sub-pocket with N-4 atom accepting an H-bond from the Asn768 residue, as expected., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with α 4 β 2 Ki value of 10 pM and a very high α 7 /α 4 β 2 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for α 4 β 2 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Aurora kinases are known to be overexpressed in various solid tumors and implicated in oncogenesis and tumor progression. A series of nicotinamide derivatives were synthesized and their biological activities were evaluated, including kinase inhibitory activity against Aur A and Aur B and in vitro antitumor activity against SW620, HT-29, NCI-H1975 and Hela cancer cell lines. In addition, the study of antiproliferation, cytotoxicity and apoptosis was performed meanwhile. As the most potent inhibitor of Aur A, 4-((3-bromo-4-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)nicotinamide (10l) showed excellent antitumor activity against SW620 and NCI-H1975 with IC 50 values were 0.61 and 1.06 μM, while the IC 50 values of reference compound were 3.37 and 6.67 μM, respectively. Furthermore, binding mode studies indicated that compound 10l forms better interaction with Aur A., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chromobox homolog 7 (Cbx7) is an epigenetic modulator that is an important driver of multiple cancers. It is a methyl reader protein that operates by recognizing and binding to methylated lysine residues on specific partners. Herein we report our efforts to create low-molecular-weight inhibitors of Cbx7 by making rational structural adaptations to inhibitors of a different methyl reader protein, L3MBTL1, inhibitors that had previously been reported to be inactive against Cbx7. We evaluated each new inhibitor for Cbx7 inhibition by fluorescence polarization assay, and also confirmed the binding of selected inhibitors to Cbx7 by saturation-transfer difference NMR spectroscopy. This work identified multiple small-molecule inhibitors with modest (IC 50 : 257-500 μm) potency., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Interest in pharmacological agents capable of increasing cellular NAD + concentrations has stimulated investigations of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). NR and NMN require large dosages for effect. Herein, we describe synthesis of dihydronicotinamide riboside (NRH) and the discovery that NRH is a potent NAD + concentration-enhancing agent, which acts within as little as 1 h after administration to mammalian cells to increase NAD + concentrations by 2.5-10-fold over control values. Comparisons with NR and NMN show that in every instance, NRH provides greater NAD + increases at equivalent concentrations. NRH also provides substantial NAD + increases in tissues when administered by intraperitoneal injection to C57BL/6J mice. NRH substantially increases NAD + /NADH ratio in cultured cells and in liver and no induction of apoptotic markers or significant increases in lactate levels in cells. Cells treated with NRH are resistant to cell death caused by NAD + -depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate. Studies to identify its biochemical mechanism of action showed that it does not inhibit NAD + consumption, suggesting that it acts as a biochemical precursor to NAD + Cell lysates possess an ATP-dependent kinase activity that efficiently converts NRH to the compound NMNH, but independent of Nrk1 or Nrk2. These studies identify a putative new metabolic pathway to NAD + and a potent pharmacologic agent for NAD + concentration enhancement in cells and tissues., (© 2019 Yang et al.)

Radiolabeled prostate-specific membrane antigen (PSMA) targeting PET-tracers have become desirable radiopharmaceuticals for the imaging of prostate cancer (PC). Recently, the PET radiotracer [ 18 F]PSMA-1007 was introduced as an alternative to [ 68 Ga]Ga-PSMA-11, for staging and diagnosing biochemically recurrent PC. We incorporated a one-step procedure for [ 18 F]PSMA-1007 radiosynthesis, using both Synthra RNplus and GE TRACERlab FxFN automated modules, in accordance with the recently described radiolabeling procedure. Although the adapted [ 18 F]PSMA-1007 synthesis resulted in repeatable radiochemical yields (55 ± 5%, NDC), suboptimal radiochemical purities of 87 ± 8% were obtained using both modules. As described here, modifications made to the radiolabeling and the solid-phase extraction purification steps reduced synthesis time to 32 minutes and improved radiochemical purity to 96.10%, using both modules, without shearing the radiochemical yield., (© 2019 John Wiley & Sons, Ltd.)

Dysfunction of GSK3 is implicated in the etiology of many brain, inflammatory, cardiac diseases, and cancer. PET imaging would enable in vivo detection and quantification of GSK3 and can impact the choice of therapy, allow non-invasive monitoring of disease progression and treatment effects. In this report, the synthesis and evaluation of a high affinity GSK3 ligand, [ 11 C]2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide, ([ 11 C]CMP, (3), (IC 50  = 3.4 nM, LogP = 1.1) is described. [ 11 C]CMP was synthesized in 25 ± 5% yield by radiomethylating the corresponding phenolate using [ 11 C]CH 3 I. The radioligand exhibited modest uptake in U251 human glioblastoma cell lines with ∼50% specific binding. MicroPET studies in rats indicated negligible blood-brain barrier (BBB) penetration of [ 11 C]CMP, despite its high affinity and suitable logP value for BBB penetration. However, administration of cyclosporine prior to [ 11 C]CMP injection showed significant improvement in brain radioactivity uptake and the tracer binding. This finding indicates that [ 11 C]CMP might be a P-gp efflux substrate and therefore has some limitations for routine in vivo PET evaluations in brain., (Copyright © 2019. Published by Elsevier Ltd.)

The voltage-gated sodium channel, Na v 1.1, is predominantly expressed in parvalbumin-positive fast spiking interneurons and has been genetically linked to Dravet syndrome. Starting from a high throughput screening hit isoxazole derivative 5, modifications of 5 via combinations of IonWorks and Q-patch assays successfully identified the nicotinamide derivative 4. Its increasing decay time constant (tau) of Na v 1.1 currents at 0.03 μM along with significant selectivity against Na v 1.2, Na v 1.5, and Na v 1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Na v 1.1 activator that can be used to analyze pathophysiological functions of the Na v 1.1 channel towards treating various central nervous system diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Nicotinamide and pyridine-containing conjugates have attracted a lot of attention in research as they have found use in a wide range of applications including as redox flow batteries and calcium channel blockers, in biocatalysis, and in metabolism. The interesting redox character of the compounds' pyridine/dihydropyridine system allows them to possess very similar characteristics to the natural chiral redox agents NAD + /NADH, even mimicking their functions. There has been considerable interest in designing and synthesizing NAD + /NADH mimetics with similar redox properties. In this research, three nicotinamide conjugates were designed, synthesized, and characterized. Molecular structures obtained through X-ray crystallography were obtained for two of the conjugates, thereby providing more detail on the bonding and structure of the compounds. The compounds were then further evaluated for biochemical properties, and it was found that one of the conjugates possessed similar functions and characteristics to the natural NADH. This compound was evaluated in the active enzyme, enoate reductase; like NADH, it was shown to help reduce the C=C double bond of three substrates and even outperformed the natural coenzyme. Kinetic data are reported., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(-)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(-)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10 µM (6 µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC 50  = 48.6 and 57.6 µM, respectively, 72 h), encouraging their further investigation as potential antimicrobials against skin and wound infections., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A novel, reversible redox-active MRI probe, GdNR1, has been developed for the study of redox changes associated with diseased states. This system exhibits switching in relaxivity upon reduction and oxidation of the appended nicotinimidium. Relaxivity studies and cyclic voltammetry confirmed the impressive reversibility of this system, at a biologically-relevant reduction potential. A 2.5-fold increase in relaxivity was observed upon reduction of the complex, which corresponds to a change in the number of inner-sphere water molecules, as confirmed by luminescence lifetimes of the Eu(iii) analogue and NMRD studies. This is the first example of a redox-responsive MRI probe utilising the biologically-inspired nicotinimidium redox switch. In the future this strategy could enable the non-invasive identification of hypoxic tissue and related cardiovascular disease.

Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight-year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, about 20 % of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR-ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation. However, ponatinib has severe cardiovascular toxicities; hence, there have been efforts to find safer CML drugs that work against ABL1 secondary mutations. We reveal that isoquinoline- or naphthyridine-based compounds, such as HSN431, HSN576, HSN459, and HSN608 potently inhibit the enzymatic activities of ABL1, ABL1(T315I), and ABL1(E255K). These compounds inhibit the proliferation of ABL1-driven CML cell lines, K652 and KCL22 as well as the drug-resistant cell line, KCL22-IR, which harbors the secondary mutated ABL1(T315I) kinase., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this concise practitioner protocol, the radiochemical synthesis of [ 18 F]FNDP suitable for human positron emission tomography studies is described and the results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice requirements., (Copyright © 2018 John Wiley & Sons, Ltd.)

As a cofactor for numerous reactions, NAD+ is found widely dispersed across many maps of cellular metabolism. This core redox role alone makes the biosynthesis of NAD+ of great interest. Recent studies have revealed new biological roles for NAD+ as a substrate for diverse enzymes that regulate a broad spectrum of key cellular tasks. These NAD+-consuming enzymes further highlight the importance of understanding NAD+ biosynthetic pathways. In this study, we developed a chemo-enzymatic synthesis of isotopically labeled NAD+ precursor, nicotinamide riboside (NR). The synthesis of NR isotopomers allowed us to unambiguously determine that NR is efficiently converted to NAD+ in the cellular environment independent of degradation to nicotinamide, and it is incorporated into NAD+ in its intact form. The versatile synthetic method along with the isotopically labeled NRs will provide powerful tools to further decipher the important yet complicated NAD+ metabolism.

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC 50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme., Competing Interests: The authors declare no conflict of interest.

Nicotinamide N-methyltransferase (NNMT) has been linked to obesity and diabetes. We have identified a novel nicotinamide (NA) analog, compound 12 that inhibited NNMT enzymatic activity and reduced the formation of 1-methyl-nicotinamide (MNA), the primary metabolite of NA by ∼80% at 2 h when dosed in mice orally at 50 mg/kg., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The rapid synthesis of two radiofluoronicotinamide derivatives, namely, [ 18 F]MEL050 and [ 18 F]MEL-2F has been simply performed starting from commercial materials. [ 18 F]MEL-2F is a new, potential analogue PET-probe for melanoma imaging. [ 18 F]MEL050 is already an excellent PET imaging probe for early specific diagnosis. The synthesis involves coupling step to obtain the precursor followed by radiofluorination. During the synthesis of the precursors different coupling reagents, such as HBTU, TFFH, HOBT, COMU and PyCIU have been applied. PyClU was found the best to reduce the coupling period to < 1h. The labeled compounds were isolated and purified by HPLC. In the in-vitro study three kinds of cells, namely, Melur (melanin free), KB-3 carcinoma cell line (non-melanoma) and B16-F10 melanoma cell line were used to evaluate the uptake of the radiotracers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The "RNA World" hypothesis proposes an early episode of the natural history of Earth, where RNA was used as the only genetically encoded molecule to catalyze steps in its metabolism. This, according to the hypothesis, included RNA catalysts that used RNA cofactors. However, the RNA World hypothesis places special demands on prebiotic chemistry, which must now deliver not only four ribonucleosides, but also must deliver the "functional" portion of these RNA cofactors. While some (e.g., methionine) present no particular challenges, nicotinamide ribose is special. Essential to its role in biological oxidations and reductions, its glycosidic bond that holds a positively charged heterocycle is especially unstable with respect to cleavage. Nevertheless, we are able to report here a prebiotic synthesis of phosphorylated nicotinamide ribose under conditions that also conveniently lead to the adenosine phosphate components of this and other RNA cofactors., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A two-step chemical method for the synthesis of β-nicotinamide riboside (NR) is described. NR has achieved wide use as an NAD + precursor (vitamin B3) and can significantly increase central metabolite NAD + concentrations in mammalian cells. β-NR can be prepared with an efficient two-step procedure. The synthesis is initiated via coupling of commercially available 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose with ethyl nicotinate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). 1 H NMR showed that the product was formed with complete stereoselectivity to produce only the β-isomer in high yield (>90% versus starting sugar). The clean stereochemical result suggests that the coupling proceeds via a cationic cis-1,2-acyloxonium-sugar intermediate, which controls addition by nucleophiles to generate predominantly β-stereochemistry. The subsequent deprotection of esters in methanolic ammonia generates the desired product in 85% overall yield versus sugar. © 2017 by John Wiley & Sons, Inc., (Copyright © 2017 John Wiley & Sons, Inc.)

A series of N-(4-alkoxy-3-cyanophenyl)isonicotinamide/nicotinamide derivatives was designed, synthesized and evaluated for inhibitory potency in vitro against xanthine oxidase. The isonicotinamide series was considerably more effective than the nicotinamide series. SARs analysis revealed that the isonicotinoyl moiety played a significant role on the inhibition and that a benzyl ether tail (e.g., ortho-cyanobenzoxy) linked to the benzonitrile moiety benefits the inhibitory potency. Among these compounds, 10q (IC 50  = 0.3 μM) was identified to be the most potent in this work and was observed to be 28.3-fold more potent than allopurinol but 20-fold less potent than topiroxostat. The Lineweaver-Burk plot showed that 10q acted as a mixed-type inhibitor on xanthine oxidase. Molecular modeling provided a reasonable explanation for the SARs observed in this study., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Alzheimer's disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of β-amyloid (Aβ), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC 50 value of 0.052 µM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC 50 values from 0.071 to 0.797 µM. Compound 3b exhibited strong Aβ 1-42 aggregation inhibitory effect with 25.7% at 5 µM to 92.8% at 100 µM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment.

Oxidoreductases are attractive biocatalysts that convert achiral substrates into products of higher value, but they are also for the most part dependent on nicotinamide cofactors. Recently, biomimetic nicotinamide derivatives have received attention as less costly alternatives to natural cofactors. However, recycling of biomimetics is still challenging because there are only limited opportunities. Here, we have characterized various biomimetic cofactors with regard to stability and redox potentials to find the best alternative to natural cofactors. Further, the cofactor spectrum of NADH oxidase from Lactobacillus pentosus (LpNox) could be expanded, and the enzymatic activity was also compared to activities with different small-molecule catalysts. As a result, we succeeded in identifying several strategies for regeneration of oxidized biomimetics., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.

Background: Succinate dehydrogenase (SDH) plays an important role in the Krebs cycle, which is considered as an attractive target for development of succinate dehydrogenase inhibitors (SDHIs) based on antifungal agents. Thus, in order to discover novel molecules with high antifungal activities, SDH as the target for a series of novel nicotinamide derivatives bearing substituted pyrazole moieties were designed and synthesised via a one-pot reaction., Results: The biological assay data showed that compound 3 l displayed the most potent antifungal activity with EC 50 values of 33.5 and 21.4 µm against Helminthosporium maydis and Rhizoctonia cerealis, respectively. Moreover, 3 l exhibited the best inhibitory ability against SDH enzymes. The results of docking simulation showed that 3 l was deeply embedded into the SDH binding pocket, and the binding model was stabilised by a cation-π interaction with Arg 43, Tyr 58 and an H-bond with Trp 173., Conclusion: The study suggests that the pyrazole nicotinamide derivative 3 l may serve as a potential SDHI that can be used as a novel antifungal agent, and provides valuable clues for the further design and optimisation of SDH inhibitors. © 2016 Society of Chemical Industry., (© 2016 Society of Chemical Industry.)

The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC 50 values ranging between 6.0 and 35.7 μM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Based on the structures of the reported compounds G884 [N-(3-(pentan-2-yloxy)phenyl)nicotinamide], E1210 [3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine], and 10 b [2-amino-N-((5-(3-fluorophenoxy)thiophen-2-yl)methyl)nicotinamide], which inhibit the biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins in fungi, a series of novel 2-aminonicotinamide derivatives were designed, synthesized, and evaluated for in vitro antifungal activity. Most of these compounds were found to exhibit potent in vitro antifungal activity against Candida albicans, with MIC 80 values ranging from 0.0313 to 4.0 μg mL -1 . In particular, compounds 11 g [2-amino-N-((5-(((2-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] and 11 h [2-amino-N-((5-(((3-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] displayed excellent activity against C. albicans, with MIC 80 values of 0.0313 μg mL -1 , and exhibited broad-spectrum antifungal activity against fluconazole-resistant C. albicans, C. parapsilosis, C. glabrata, and Cryptococcus neoformans, with a MIC 80 range of 0.0313-2.0 μg mL -1 . Further studies by electron microscopy and laser confocal microscopy indicated that compound 11 g targets the cell wall and decreases GPI anchor content on the cell surface of C. albicans., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[ 11 C]methoxypyridin-3-yl)isonicotinamide ([ 11 C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[ 11 C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([ 11 C]7a) were prepared from the precursors (4b and 7b) with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370-1110GBq/μmol with a total synthesis time of ∼40-min from EOB., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Two series of Sorafenib derivatives bearing phenylpyrimidine-carboxamide moiety (16a-g and 17a-p) were designed, synthesized and evaluated for the IC 50 values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC 50 values of 6.35±0.43μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC 50 values of 3.39±0.37μM. Structure-activity relationships (SARs) and docking studies indicated that the second series (17a-p) showed more active than the first series (16a-g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Melanoma is a highly malignant cutaneous tumor of melanin-producing cells. MEL050 is a synthetic benzamide-derived molecule that specifically binds to melanin with high affinity. Our aim was to implement a fully automated radiosynthesis of [ 18 F]MEL050, using for the first time, the AllInOne™ synthesis module (Trasis), and to evaluate the potential of [ 18 F]MEL050 for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases, and to compare it with that of [ 18 F]FDG., Methods: Automated radiosynthesis of [ 18 F]MEL050, including HPLC purification and formulation, were performed on an AllInOne™ synthesis module. [ 18 F]MEL050 was synthesized using a one-step bromine-for-fluorine nucleophilic heteroaromatic substitution. Melanoma models were induced by subcutaneous (primary tumor) or intravenous (pulmonary metastases) injection of B16-F10-luc2 cells in NMRI mice. The maximum percentage of [ 18 F]MEL050 Injected Dose per g of lung tissue (%ID/g Max) was determined on PET images, compared to [ 18 F]FDG and correlated to in vivo bioluminescence imaging., Results: The automated radiosynthesis of [ 18 F]MEL050 required an overall radiosynthesis time of 48min, with a yield of 13-18% (not-decay corrected) and radiochemical purity higher than 99%. [ 18 F]MEL050 PET/CT images were concordant with bioluminescence imaging, showing increased radiotracer uptake in all primary subcutaneous tumors and pulmonary metastases of mice. PET quantification of radiotracers uptake in tumors and muscles demonstrated similar tumor-to-background ratio (TBR) with [ 18 F]MEL050 and [ 18 F]FDG in subcutaneous tumors and higher TBR with [ 18 F]MEL050 than with [ 18 F]FDG in pulmonary metastases., Conclusion: We successfully implemented the radiosynthesis of [ 18 F]MEL050 using the AllInOne™ module, including HPLC purification and formulation. In vivo PET/CT validation of [ 18 F]MEL050 was obtained in mouse models of pigmented melanoma, where higher [ 18 F]MEL050 uptake was observed in sub-millimetric pulmonary metastases, comparatively to [ 18 F]FDG., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Chirality greatly influences the biological and pharmacological properties of a pesticide and will contribute to unnecessary environmental loading and undesired ecological impact. No structure and activity relationship (SAR) of enantiopure succinate dehydrogenase inhibitors (SDHIs) was documented during the structure optimization of boscalids. On the basis of commercial SDHIs, oxazoline natural products, and versatile oxazoline ligands in organic synthesis, the first effort was devoted to explore the chiral SDHIs and the preliminary mechanism thereof. Fine-tuning furnished chiral nicotinamides 4ag as a more promising fungicidal candidate against Rhizoctonia solani, Botrytis cinerea, and Sclerotinia sclerotiorum, with EC 50 values of 0.58, 0.42, and 2.10 mg/L, respectively. In vivo bioassay and molecular docking were investigated to explore the potential in practical application and plausible novelty in action mechanism, respectively. The unexpected molecular docking model showed the different chiral effects on the binding site with the amino acid residues. This chiral nicotinamide also featured easy synthesis and cost-efficacy. It will provide a powerful complement to the commercial SDHI fungicides with the introduction of chirality.

Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC 50 values of 0.56±0.83μM, 3.88±1.03μM and 3.15±0.81μM, which were 1.03-6.14-fold more active than sorafenib (3.44±1.50μM, 3.18±1.43μM, 3.24±0.45μM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC 50 value was 0.72μM. Structure-activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Previously (Karade et al., 2014), we have reported the synthesis and in vitro evaluation of bis-pyridinium derivatives of pyridine-3-yl-(2-hydroxyimino acetamide), as reactivators of sarin and VX inhibited hAChE. Few of the molecules showed superior in vivo protection efficacy (mice model) (Kumar et al., 2014; Swami et al., 2016) in comparison to 2-PAM against DFP and sarin poisoning. Encouraged by these results, herein we report the synthesis and in vitro evaluation of isonicotinamide derivatives of pyridine-3-yl-(2-hydroxyimino acetamide) (4a-4d) against sarin and VX inhibited erythrocyte ghost hAChE. Reactivation kinetics of these compounds was studied and the determined kinetic parameters were compared with that of commercial reactivators viz. 2-PAM and obidoxime. In comparison to 2-PAM and obidoxime, oxime 4a and 4b exhibited enhanced reactivation efficacy toward sarin inhibited hAChE while oxime 4c showed far greater reactivation efficacy toward VX inhibited hAChE. The acid dissociation constant and IC50 values of these oximes were determined and correlated with the observed reactivation potential., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.

Nicotinamide (a vitamin B3 amide) is one of the key vitamins as well as a drug for treatment of M. tuberculosis, HIV, cancer, and other diseases. Here, an improved Zincke reaction methodology is presented allowing for straightforward and scalable synthesis of nicotinamide-1-(15)N with an excellent isotopic purity (98%) and good yield (55%). (15)N nuclear spin label in nicotinamide-1-(15)N can be NMR hyperpolarized in seconds using parahydrogen gas. NMR hyperpolarization using the process of temporary conjugation between parahydrogen and to-be-hyperpolarized biomolecule on hexacoordinate iridium complex via the Signal Amplification By Reversible Exchange (SABRE) method significantly increases detection sensitivity (e.g., >20,000-fold for nicotinamide-1-(15)N at 9.4 T) as has been shown by Theis T. et al. (J. Am. Chem. Soc. 2015, 137, 1404), and hyperpolarized in this fashion, nicotinamide-1-(15)N can be potentially used to probe metabolic processes in vivo in future studies. Moreover, the presented synthetic methodology utilizes mild reaction conditions, and therefore can also be potentially applied to synthesis of a wide range of (15)N-enriched N-heterocycles that can be used as hyperpolarized contrast agents for future in vivo molecular imaging studies.

Isonicotinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to play critical roles in affinity for serotoninergic receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(3-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)propyl)isonicotinamide (4s) with Ki = 0.130 nM, was the most active and selective derivative for the 5-HT1A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors. Compound 4o, instead, showed 5-HT2A affinity values in subnamolar range. Moreover, the compounds having better affinity and selectivity binding profile towards 5-HT1A and 5-HT2A receptors were selected in order to be tested by in vitro and in vivo assays to determine their functional activity., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: The field of coordination chemistry has registered a phenomenal growth during the last few decades. It is well known that precious metals have been used for medicinal purposes for at least 3500 years. At that time, precious metals were believed to benefit health because of their rarity, but research has now well established the link between medicinal properties of inorganic drugs and specific biological properties., Methods: The current study was designed to explain the synthesis and characterization of the lanthanide (III) nitrate complexes with N-(2-hydroxynaphthalen-1-yl) methylene) nicotinohydrazide schiff base and to evaluate the antibacterial and the antioxidant activities of the schiff base and it's lanthanide ion complexes. Antimicrobial activity of the Lanthanide (III) nitrate complexes with N-(2- hydroxynaphthalen-1-yl) methylene) nicotinohydrazide schiff base was estimated by minimum inhibitory concentration (MIC, µg/mL) using a micro-broth dilution method for different clinical isolates such as Eschereshia coli and Enterococcus faecalis. The antioxidant activities of the ligand and its lanthanide complexes were tested using a UV-Visible spectrophotometer by preparing 5x10-4M of all tested samples and DPPH in Dimethyl sulphoxide (DMSO)., Results: Our present study has shown that moderate antimicrobial activity exists against both ligand and its complexes. There was no significant difference between Gram-positive and Gram-negative bacteria towards the tested ligand and its complexes. The free ligand has scavenging activity between 13-21 % while all complexes are more efficient in quenching DPPH than free ligand., Conclusion: The results obtained herein indicate that the ligand and its complexes have a considerable antibacterial activity as well as antioxidant activity in quenching DPPH., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brain-penetrant compound 14G: [5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-[(1R,2R)-2-hydroxy-cyclohexyl]-3-pyridinecarboxamide] and its peripherally restricted analog 14H: [5-(4-chlorophenyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-6-(2-methoxyethoxy)-3-pyridinecarboxamide], have been recently introduced as selective, high-affinity antagonists of the human cannabinoid-1 receptor (hCB1R). Binding analyses revealed two orders of magnitude lower affinity of these compounds for mouse and rat versus human CB1R, whereas the affinity of rimonabant is comparable for all three CB1Rs. Modeling of ligand binding to CB1R and binding assays with native and mutant (Ile105Met) hCB1Rs indicate that the Ile105 to Met mutation in rodent CB1Rs accounts for the species-dependent affinity of 14G: and 14H: . Our work identifies Ile105 as a new pharmacophore component for developing better hCB1R antagonists and invalidates rodent models for assessing the antiobesity efficacy of 14G: and 14H: ., (U.S. Government work not protected by U.S. copyright.)

Purpose: We investigated the RESS process as a means of simultaneous micronization and cocrystallization of a model drug with poor aqueous solubility., Methods: 1:1 cocrystals of ibuprofen (IBU) and nicotinamide (NA) were produced with a pilot scale unit for RESS processing.IBU and NA were dissolved in scCO2 at 30 MPa and 50°C. After 24 h, the supercritical solution was expanded at a medium CO2 flow rate of 3.8 kg/h during 60 min into an expansion vessel kept at ambient conditions. Cocrystals were identified with DSC, XRD and confocal Raman microscopy (CRM) and further characterized by SEM, specific surface area, wetting ability, solubility and dissolution testing., Results: Judging by DSC, XRD and CRM, cocrystals with high purity could be produced with the RESS technique. Micronization via RESS was successful, since the specific surface area of RESS cocrystals was increased almost tenfold in comparison to cocrystals produced by slow solvent evaporation. Due to the additional micronization, the mean dissolution time of IBU from RESS cocrystals was decreased., Conclusions: RESS cocrystallization offers the advantage of combining micronization and cocrystallization in a single production step. For drugs with dissolution-limited bioavailability, RESS cocrystallization may therefore be a superior approach in comparison to established cocrystallization techniques.

A series of 2-(1H-imidazol-2-yl) pyridine derivatives (CLW01-CLW31) have been designed and synthesized, and they were screened for BRAF kinase inhibitory activity. Besides, their biological activities were evaluated in vitro and in vivo. All the compounds were reported for the first time, and compounds CLW14 and CLW27 displayed the most potent antiproliferative activity against cell line A375 in vitro, with IC50 values of 4.26 and 2.93 μM, respectively, which were comparable with the positive control Sorafenib. Those two compounds were further evaluated for the in vivo efficacy using an A375 xenograft nude mice model. The results showed that the growth of A375 cancer cells xenografts was suppressed by factors of 35.68% and 42.50% (percent tumor growth inhibition values) after intragastric (ig) administration of compound CLW14 and CLW27 at concentration of 50 mg/kg. Thus they may be promising lead compounds to be developed as an alternative for current Sorafenib therapy., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The zinc (II) complex with nicotinamide, (C₆H₁₁N₂)[ZnBr₃(C₆H₆N₂O)], was prepared under ionothermal condition by using the ionic liquid 1-ethyl-3-methylimidazolium bromide ([EMIM]Br) as a solvent. At the same time, [EMIM]Br also functions as a structure-directing agent, leading to a framework structure different from those obtained by the conventional methods. Single-crystal X-ray analysis revealed that the coordinated compound crystallizes in monoclinic space group P2(1)/c, and the Zn (II) ion is four-coordinated by one pyridine ring N atom and three bromide anions in a slightly distorted tetrahedron arrangement. The [EMIM](+) cations acting as the extra framework charge balancing species occupy the channels of this asymmetric unit. In the crystal structure, intermolecular NH⋯Br and NH⋯O hydrogen bonds link the molecules to form a supramolecular structure. In addition, this compound was further characterized by FT-IR and Raman spectroscopic techniques, and the observed important bands were assigned. Thermogravimetric analysis (TG), Differential Scanning Calorimetry (DSC) and fluorescent properties of solid samples were also studied at room temperature., (Copyright © 2014 Elsevier B.V. All rights reserved.)