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The present article describes the synthesis of an isonicotinate-derived meso -arylporphyrin, that has been fully characterized by spectroscopic methods (including fluorescence spectroscopy), as well as elemental analysis and HR-MS. The structure of an n -hexane monosolvate has been determined by single-crystal X-ray diffraction analysis. The radical scavenging activity of this new porphyrin against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical has been measured. Its antifungal activity against three yeast strains ( C. albicans ATCC 90028, C. glabrata ATCC 64677, and C. tropicalis ATCC 64677) has been tested using the disk diffusion and microdilution methods. Whereas the measured antioxidant activity was low, the porphyrin showed moderate but encouraging antifungal activity. Finally, a study of its effect on the germination of lentil seeds revealed interesting allelopathic properties.

The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR Mycobacterium tuberculosis ( M.tb ) strains were performed. It demonstrated an MIC 50 value of 1.86 ± 0.21 μM for laboratory pathogenic M.tb strain H37Rv and 3.045 ± 0.813 μM for a clinical M.tb strain CDC1551. UH-NIP-16 also decreased the MIC 50 values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR M.tb strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse M.tb proteins showed high binding affinities with multiple M.tb proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against M.tb , both alone and in combination with first-line drugs.

Farnesoid X receptor (FXR) is a bile acid-related nuclear receptor and is considered a promising target to treat several liver disorders. Cilofexor is a selective FXR agonist and has already entered phase III trials in primary sclerosing cholangitis (PSC) patients. Pruritis caused by cilofexor treatment is dose dependent. The binding characteristics of cilofexor with FXR and its pruritogenic mechanism remain unclear. In our research, the affinity of cilofexor bound to FXR was detected using an isothermal titration calorimetry (ITC) assay. The binding mechanism between cilofexor and FXR-LBD is explained by the cocrystal structure of the FXR/cilofexor complex. Structural models indicate the possibility that cilofexor activates Mas-related G protein-coupled receptor X4 (MRGPRX4) or G protein-coupled bile acid receptor 1 (GPBAR1), leading to pruritus. In summary, our analyses provide a molecular mechanism of cilofexor binding to FXR and provide a possible explanation for the dose-dependent pruritis of cilofexor., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5-2 µg/ml). Furthermore, compounds 8b , 8d , 8f , 8k , 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure-activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.

Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (K inic ), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 K inic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone K inic , while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone K inic relaxes chromatin structure and promotes gene transcription. INH-mediated histone K inic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that K inic is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans., (© 2021. The Author(s).)

Histone lysine demethylase 4D (KDM4D), also known as JMJD2D, plays an important role in cell proliferation and survival and has been associated with several tumor types. KDM4D has emerged as a potential target for the treatment of human cancer. Here, we reported crystal complex structures for two KDM4D inhibitors, OWS [2-(1H-pyrazol-3-yl)isonicotinic acid] and 10r (5-hydroxy-2-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile), which were both determined to 2.0 Å. OWS is a newly discovered KDM4D inhibitor (IC 50  = 4.28 μM) and the critical pharmacophores of this compound are confirmed by the complex structure. Compound 10r is a KDM4D inhibitor reported by us previously. To clarify the binding mode in more detail, the crystal structure was determined and the comparison analysis revealed unique interactions that had never been observed before. Overall, our data provide new structural insights for rational design and offer an opportunity for optimization of KDM4D inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

In search of anti-inflammatory compounds, novel scaffolds containing isonicotinoyl motif were synthesized via an efficient strategy. The compounds were screened for their in vitro anti-inflammatory activity. Remarkably high activities were observed for isonicotinates 5 - 6 and 8a - 8b . The compound 5 exhibits an exceptional IC 50 value (1.42 ± 0.1 µg/mL) with 95.9% inhibition at 25 µg/mL, which is eight folds better than the standard drug ibuprofen (11.2 ± 1.9 µg/mL). To gain an insight into the mode of action of anti-inflammatory compounds, molecular docking studies were also performed. Decisively, further development and fine tuning of these isonicotinates based scaffolds for the treatment of various aberrations is still a wide-open field of research.

Background: A major focus of tuberculosis drug discovery is aimed at the development of novel antibiotics with activity against drug-resistant strains of Mycobacterium tuberculosis . Results: We have synthesized ten isoniazid derivatives and investigated for antibacterial activity toward M. tuberculosis H37Rv and isoniazid-resistant strain SRI 1369. It was revealed that only one compound, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide ( 1 ), is active toward isoniazid-resistant strain with minimum inhibitory concentration value of 0.14 μM. This compound is not cytotoxic toward human liver cells (HepG2; IC 50 >100 μM), demonstrates good permeability in Caco-2 cells. Accordingly to the results of plasma protein binding assay, unbound fraction of compound 1 , which potentially exhibits pharmacologic effects, is 57.9%. Conclusion: Therefore, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide is a promising compound for further preclinical studies.

Chagas disease is caused by Trypanosoma cruzi infection and represents an important public health concern in Latin America. Macrophages are one of the main infiltrating leukocytes in response to infection. Parasite persistence could trigger a sustained activation of these cells, contributing to the damage observed in this pathology, particularly in the heart. HP 24 , a pyridinecarboxylic acid derivative, is a new PPARγ ligand that exerts anti-inflammatory and pro-angiogenic effects. The aim of this work was to deepen the study of the mechanisms involved in the pro-angiogenic and anti-inflammatory effects of HP 24 in T. cruzi -infected macrophages, which have not yet been elucidated. We show for the first time that HP 24 increases expression of VEGF-A and eNOS through PI3K/AKT/mTOR and PPARγ pathways and that HP 24 inhibits iNOS expression and NO release, a pro-inflammatory mediator, through PPARγ-dependent mechanisms. Furthermore, this study shows that HP 24 modulates H 2 O 2 production in a PPARγ-dependent manner. It is also demonstrated that this new PPARγ ligand inhibits the NF-κB pathway. HP 24 inhibits IKK phosphorylation and IκB-α degradation, as well as p65 translocation to the nucleus in a PPARγ-dependent manner. In Chagas disease, both the sustained increment in pro-inflammatory mediators and microvascular abnormalities are crucial aspects for the generation of cardiac damage. Elucidating the mechanism of action of new PPARγ ligands is highly attractive, given the fact that it can be used as an adjuvant therapy, particularly in the case of Chagas disease in which inflammation and tissue remodeling play an important role in the pathophysiology of this disease., (Copyright © 2020 Penas, Carta, Cevey, Rada, Pieralisi, Ferlin, Sales, Mirkin and Goren.)

Pharmacological options to treat canine babesiosis caused by Babesia gibsoni, are limited. To address this challenge, screening for novel drug candidates and drug targets against B. gibsoni is urgently needed. In this study, we explored the inhibitory effects of two phytohormone inhibitors, fluridone (FLU) and inabenfide (INA), against B. gibsoni in vitro. The half-maximal inhibitory concentration (IC 50 ) values of FLU and INA against B. gibsoni were 60.6 ± 3.4 and 4.3 ± 0.3 μM, respectively. Parasitemia and viability at 24, 48, and 72 h after FLU and INA treatments were significantly lower than those in the control group. The cytotoxicity of FLU and INA was evaluated using the dog-derived Madin-Darby canine kidney (MDCK) cell line; both FLU and INA were less toxic to the MDCK cells than to the control cells. The selectivity index of FLU and INA were higher than 16.5 and 232.6, respectively. In summary, the present study demonstrated that FLU and INA were effective against B. gibsoni infection in vitro and that these compounds might have potential as candidate drugs for the treatment of B. gibsoni., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Nicotinic and isonicotinic thiosemicarbazide or hydrazine carbothioamides 3-27 were synthesized and the structures of synthetic compounds were elucidated by various spectroscopic techniques such as EI-MS, 1 H-, and 13 C NMR. Synthetic derivatives were evaluated for their urease inhibitory activity which revealed that except few all derivatives demonstrated excellent inhibition in the range of IC 50 values of 1.21-51.42 μM as compared to the standard thiourea (IC 50  = 21.25 ± 0.13 μM). Among the twenty-five synthetic derivatives nineteen 1-5, 7, 8, 10, 12, 14-18, 20-22, 24-27 were found to be more active showing IC 50 values between 1.13 and 19.74 μM showing superior activity than the standard. Limited structure-activity relationship demonstrated that the positions of substituent as well as position of nitrogen in pyridine ring are very important for inhibitory activity of this class of compound. To verify these interpretations, in silico study was also performed. A good correlation was obtained between the biological evaluation of active compounds and docking study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study describes the synthesis, lipophilicity and in vitro antimicrobial assays of 15 new hydrazide-hydrazones of isonicotinic acid. New derivatives were obtained on the basis of the condensation reaction of isonicotinic acid hydrazide with different aromatic aldehydes. The chemical structure of synthesized compounds was confirmed by spectral methods. Experimental lipophilicity of new isonicotinic acid derivatives was determined using reversed-phase thin-layer chromatography. All synthesized compounds were subjected to in vitro antimicrobial assays against reference strains of Gram-positive bacteria, Gram-negative bacteria and fungi belonging to Candida spp. Some of the synthesized hydrazide-hydrazones proved to be significant antibacterial compounds and more potent than commonly used chemotherapeutic agents., (© 2017 John Wiley & Sons A/S.)

With only a single class of antiviral drugs existing for treatment of influenza (neuraminidase inhibitors), the search for novel effective compounds is urgently needed. We evaluated a low molecular mass compound, enisamium iodide (FAV00A), against influenza virus infections in primary differentiated normal human bronchial epithelial (NHBE) cells, and in ferrets. FAV00A (500 µg/ml) markedly inhibited influenza virus replication and reduced viral M-gene expression in NHBE cells. Treatment of ferrets with FAV00A (200 mg/kg once daily for 7 days) initiated 24 h after inoculation with 105 TCID50 of influenza A/Wisconsin/67/2005 (H3N2) virus resulted in a significant decrease in virus titers in the upper respiratory tract. Our data show that FAV00A exhibits an antiviral effect against influenza virus in NHBE cells and provides some benefits in a ferret model. Thus, further Keywords: antiviral agents; enisamium iodide; influenza virus; MDCK cells; NHBE cells; ferrets.

Hyperlipidemia and oxidative stress have been implicated as contributing factors to the development of atherosclerosis and cardiovascular diseases (CVDs). Currently, a large number of antihyperlipidemic medications are conveniently available in the market. Nonetheless, the majority of antihyperlipidemics lack the desired safety and efficacy. Thus, the present study was undertaken to evaluate the potential effect of novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives in controlling hyperlipidemia and oxidative stress using the Triton WR-1339-induced hyperlipidemic rat model for antihyperlipidemic activity and the DPPH radical scavenging assay for antioxidant activity. This study revealed the antihyperlipidemic activities of some of the newly synthesized, novel carboxamide derivatives, mainly C4 and C12 (p < 0.05). The majority of the compounds displayed a relatively low or no DPPH radical scavenging effect, with C20 possessing the best radical scavenging effect (22%) among all. This research opens the door for new potential antihyperlipidemic compounds derived from isonicotinic acid. N-(3-Benzoylphenyl)pyridine-4-carboxamide (C4) was found to have promising lipid-lowering and antioxidant effects, which may create a protective effect against CVDs, by reducing the LDL-C levels and diminishing the generation of reactive oxygen species., (© 2017 Deutsche Pharmazeutische Gesellschaft.)

The prochelator BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) contains a boronate group that prevents metal coordination until reaction with peroxide releases the iron chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide). BSIH exists in aqueous buffer and cell culture media in equilibrium with its hydrolysis products isoniazid and (2-formylphenyl)boronic acid (FBA). The relative concentrations of these species limit the yield of intact SIH available for targeted iron chelation. While the hydrolysis fragments are nontoxic to retinal pigment epithelial cells, these results suggest that modifications to BSIH that improve its hydrolytic stability yet maintain its low inherent cytotoxicity are desirable for creating more efficient prochelators for protection against cellular oxidative damage., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Isonicotinyl and pyrazinyl ferrocenyl-derived complexes were prepared using various hydrazides and ferrocenyl aldehydes. Three heterobimetallic complexes were also synthesized from the Schiff base-derived isonicotinyl ferrocene complex using various platinum group metal dimers based on ruthenium, rhodium and iridium. All complexes were evaluated in vitro for antimycobacterial and antiparasitic activity. Against Mycobacterium tuberculosis H37Rv, the platinum group metal complexes showed glycerol-dependent antimycobacterial activity. The antiplasmodial activities against the NF54 chloroquine-sensitive strain of Plasmodium falciparum of some compounds were moderate, while some complexes also showed promising activity against Trichomonas vaginalis. Incorporation of the ferrocenyl-salicylaldimine moiety resulted in enhanced antimicrobial activity compared to the non-ferrocenyl compound in some cases. The bimetallic iridium-ferrocene isonicotinyl complex exhibited superior antitrichomonal activity relative to its organic counterpart, isoniazid. Furthermore, all these compounds, when screened on several normal flora bacteria of humans, showed no effect on the microbiome, emphasizing the selection of these compounds for these pathogens. The promising antimicrobial activities of the complexes thus supports incorporation of ferrocene as part of existing antimicrobial therapies in order to alter their biological activities favorably.

The enzyme - enoyl acyl carrier protein reductase (enoyl ACP reductase) is a validated target for antitubercular activity. Inhibition of this enzyme interferes with mycolic acid synthesis which is crucial for Mycobacterium tuberculosis cell growth. In the present work 2D and 3D quantitative structure activity relationship (QSAR) studies were carried out on a series of thiazinan-Isoniazid pharmacophore to design newer analogues. For 2D QSAR, the best statistical model was generated using SA-MLR method (r 2 =0.958, q 2 =0.922) while 3D QSAR model was derived using the SA KNN method (q 2 =0.8498). These studies could guide the topological, electrostatic, steric, hydrophobic substitutions around the nucleus based on which the NCEs were designed. Furthermore, molecular docking was performed to gauze the binding affinity of the designed analogues for enoyl ACP reductase enzyme. Amongst all the designed analogues the binding energies of SKS 01 and SKS 05 were found to be -5.267kcal/mol and -5.237kcal/mol respectively which was comparable with the binding energy of the standard Isoniazid (-6.254kcal/mol)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The polychlorinated compounds captafol (CPL) and 2,6-dichloroisonicotinic acid (INA) are able to protect plants acting as a fungicide or an inductor of plant resistance, respectively. At the same time, CPL and INA are dangerous for the respiratory organisms, i.e. mammalians, bacteria, and fungi. The high electron-withdrawing ability of these compounds enables them to serve as unnatural electron acceptors in the cellular ambient near to electron transport pathways located in the thylakoid membrane of chloroplasts or in the mitochondrial respiratory chain. Low-energy electron attachment to CPL and INA in vacuo leads to formation of many fragment species mainly at thermal electron energy as it is shown using dissociative electron attachment spectroscopy. On the basis of the experimental findings, assigned with the support of density functional theory calculations it is suggested that the different bioactivity of CPL and INA in respiratory and photosynthetic organisms is due to the interplay between the dissociative electron attachment process and the energies of electrons leaked from the electron transport pathways.

Background: Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition., Methods & Results: Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3., Conclusion: Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.

c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.

A novel isonicotic acid hydrazide Schiff base derivative N'-(3,5-di-tert-butyl-2-hydroxy-benzylidene) isonicotinohydrazide (DHIH) has been synthesized and developed as a high selective and sensitive colorimetric probe for Cu(2+) determination. Addition of Cu(2+) to the solution of DHIH resulted in a rapid color change from colorless to yellow together with an obvious new absorption band appeared at the range of 400-440 nm by forming a 1:1 complex. Experimental results indicated that the DHIH could provide absorption response to Cu(2+) with a linear dynamic range from 1.0×10(-5) to 1.0×10(-4)mol/L. The detection limit of Cu(2+) was 5.24×10(-7)mol/L with good tolerance of other metal ions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A putative antibacterial and antifungal compound, (R)-2-methylheptyl isonicotinate, was synthesized via reductive lactone alkylation of (R)-4-methyldihydrofuran-2(3H)-one. Structural characterisation data as well as bioassay results (with Bacillus subtilis or Escherichia coli) contradict those previously reported., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

UVA radiation can damage cells and tissues by direct photodamage of biomolecules as well as by initiating metal-catalyzed oxidative stress. In order to alleviate both concerns simultaneously, we synthesized a multifunctional prochelator PC-HAPI (2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (trans)-3-(2,4-dihydroxyphenyl)acrylate) that contains a trans-(o-hydroxy)cinnamate ester photocleavable protecting group that is cleaved upon UVA exposure to release a coumarin, umbelliferone, and an aroylhydrazone metal chelator, HAPI (N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide). While the prochelator PC-HAPI exhibits negligible affinity for iron, it responds rapidly to UVA irradiation and converts to an iron-binding chelator that inhibits iron-catalyzed formation of reactive oxygen species and protects cells from UVA damage., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Our previous studies showed that several sipholane triterpenes, sipholenol A, sipholenone E, sipholenol L and siphonellinol D, have potent reversal effect for multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp/ABCB1). Through comparison of cytotoxicity towards sensitive and multi-drug resistant cell lines, we identified that the semisynthetic esters sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate potently reversed P-gp-mediated MDR but had no effect on MRP1/ABCC1 and BCRP/ABCG2-mediated MDR. The results from [3H]-paclitaxel accumulation and efflux studies suggested that these two triterpenoids were able to increase the intracellular accumulation of paclitaxel by inhibiting its active efflux. In addition, western blot analysis revealed that these two compounds did not alter the expression levels of P-gp when treated up to 72 h. These sipholenol derivatives also stimulated the ATPase activity of P-gp membranes, which suggested that they might be substrates of P-gp. Moreover, in silico molecular docking studies revealed the virtual binding modes of these two compounds into human homology model of P-gp. In conclusion, sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate efficiently inhibit the P-gp and may represent potential reversal agents for the treatment of multidrug resistant cancers.

In this work, the molecular conformation, vibrational and electronic analysis of isonicotinic acid N-oxide (iso-NANO) were presented in the ground state using experimental techniques (FT-IR, FT-Raman and UV) and density functional theory (DFT) employing B3LYP exchange correlation with the 6-311++G(d,p) basis set. The geometry optimization and energies associated possible two conformers (Rot-I and Rot-II) were computed. The vibrational spectra were calculated and fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. The obtained structures were analyzed with the Atoms in Molecules (AIMs) methodology. The computational results diagnose the most stable conformer of iso-NANO as the Rot-I form. Total density of state (TDOS) and partial density of state (PDOS) and also overlap population density of state (OPDOS) diagrams analysis for the most stable conformer (Rot-I) were calculated using the same method. Thermodynamic properties (heat capacity, entropy and enthalpy) of the title compound at different temperatures were calculated. As a result, the optimized geometry and calculated spectroscopic data show a good agreement with the experimental results., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Serum creatinine is commonly used as a marker of renal function, but increases in serum creatinine might not represent changes in glomerular filtration rate (GFR). INCB039110 (2-(3-(4-(7H-pyrrolo[2,3-day]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile) is an inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a phase 1 study, a modest and reversible increase in serum creatinine was observed after treatment with INCB039110. However, a dedicated renal function study with INCB039110, assessed by iohexol plasma clearance, conducted in healthy volunteers indicated no change in GFR. In vitro studies were therefore conducted to investigate the interaction of INCB039110 with five transporters that are likely involved in the renal clearance of creatinine. Cell systems expressing individual or multiple transporters were used, including a novel quintuple-transporter model OAT2/OCT2/OCT3/MATE1/MATE2-K. INCB039110 potently inhibited OCT2-mediated uptake of creatinine as well as MATE1-/MATE2-K-mediated efflux of creatinine. Given the interactions of INCB039110 with multiple transporters affecting creatinine uptake and efflux, an integrated system expressing all five transporters was sought; in that system, INCB039110 caused a dose-dependent decrease in transcellular transport of creatinine with weaker net inhibition compared with the effects on individual transporters. In summary, a molecular mechanism for the increase in serum creatinine by INCB039110 has been established. These studies also underline the limitations of using serum creatinine as a marker of renal function., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

In this present study, an organic compound Isonicotinic acid methyl ester (INAME) was structurally characterized by FTIR, FT-Raman, and NMR and UV spectroscopy. The optimized geometrical parameters and energies of all different and possible conformers of INAME are obtained from Density Functional Theory (DFT) by B3LYP/6-311++G(d,p) method. There are three conformers (SI, SII-1, and SII-2) for this molecule (ground state). The most stable conformer of INAME is SI conformer. The molecular geometry and vibrational frequencies of INAME in the ground state have been calculated by using HF and density functional method (B3LYP) 6-311++G (d,p) basis set. Detailed vibrational spectral analysis has been carried out and assignments of the observed fundamental bands have been proposed on the basis of peak positions and relative intensities. The computed vibrational frequencies were compared with the experimental frequencies, which yield good agreement between observed and calculated frequencies. A study on the electronic properties, such as HOMO and LUMO energies were performed by time independent DFT approach. Besides, molecular electrostatic potential (MEP) and thermodynamic properties were performed. The electric dipole moment (μ) and first hyper polarizability (β) values of the investigated molecule were computed using ab initio quantum mechanical calculations. The calculated results show that the INAME molecule may have microscopic nonlinear optical (NLO) behavior with non zero values. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by gauge independent atomic orbital (GIAO) method., (Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

The reaction between 2,5-hexanedione and isonicotinic acid hydrazide in EtOH gave two products. The ethanol insoluble product was identified as 2,5-hexanedione bis(isonicotinylhydrazone) [HINH] and the soluble ethanol product as N-(2,5-dimethyl-1H-pyrrol-1-yl)isonicotinamide [DINA]. A series of Cr(3+), Fe(3+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Pd(2+) complexes of HINH and Co(2+), Cu(2+), Zn(2+) and Hg(2+) complexes of DINA have been synthesized and structurally characterized. Based on the elemental analysis, mass spectra and molar conductance, the complexes have assigned the proposed imperical formulae. The crystal structures of N-(2,5-dimethyl-1H-pyrrol-1-yl)isonicotinamide and its Zn(2+) and Hg(2+) complexes have been solved by X-ray diffraction having [Zn(DINA)2Cl2] and [Hg(DINA)2Cl2] in a tetrahedral structure. In the DINH complexes, the ligand coordinates as a monodentate through the pyridine nitrogen. On the other hand, HINH behaves as a tetradentate (neutral or binegative) manner with the two metal ions. The magnetic moments and electronic spectra of all complexes provide tetrahedral, square-planar, trigonal biyramid and/or octahedral structure. The thermal decomposition of the complexes revealed the outer and inner solvents as well as the end product. The steady part of [Zn(DINA)2Cl2] and [Hg(DINA)2Cl2] thermograms till 303 and 286 °C indicates the absence of any outside solvents. All compounds have activity against bacteria more than fungi. [Cd4(HINH)Cl8]·3H2O has the highest values., (Copyright © 2015 Elsevier B.V. All rights reserved.)

3-Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3-dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug-like aromatic analogues of the most potent inhibitors. A range of carbon-carbon linked biaryl analogues were prepared to investigate the effect of hydrogen bond acceptor and donor patterns on inhibition. These exhibited inhibitory activity in the high-micromolar range. The addition of flexible linkers in the compounds led to the identification of more potent 3-nitrobenzylgallate- and 5-aminoisophthalate-based analogues., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The rotational spectra of laser ablated picolinic and isonicotinic acids have been studied using broadband chirped pulse (CP-FTMW) and narrowband molecular beam (MB-FTMW) Fourier transform microwave spectroscopies. Two conformers of picolinic acid, s-cis-I and s-cis-II, and one conformer of isonicotinic acid have been identified through the analysis of their rotational spectra. The values of the inertial defect and the quadrupole coupling constants obtained for the most stable s-cis-I conformer of picolinic acid, evidence the formation of an O-H···N hydrogen bond between the acid group and the endocyclic N atom. The stabilization provided by this hydrogen bond compensates the destabilization energy due to the adoption of a -COOH trans configuration in this conformer. Its rs structure has been derived from the rotational spectra of several (13)C, (15)N, and (18)O species observed in their natural abundances. Mesomeric effects have been revealed by comparing the experimental values of the (14)N nuclear quadrupole coupling constants in the isomeric series of picolinic, isonicotinic, and nicotinic acids.

Three CdS materials with different shapes (i.e., irregular, rod-like, and elongated hexagonal-pyramid) were hydrothermally synthesized through controlling the molar ratio of Cd(2+) to thiourea. Electrochemical experiments showed that the elongated hexagonal-pyramid CdS (eh-CdS) modified on glassy carbon electrode (GCE) had the higher electrical conductivity than the other two forms. Then the eh-CdS modified GCE was further modified with a layer of poly-isonicotinic acid (PIA) through electro-polymerization in IA solution to enhance the stability and functionality of the interface. The layer-by-layer modification process was characterized by atomic force microscopy and electrochemistry. Then 5'-amino functionalized DNA was immobilized on the electrode surface through coupling with the carboxylic groups derived from PIA-eh-CdS composite film. The hybridization performance of the developed biosensor was evaluated using methylene blue as redox indicator, and the results showed that the peak currents of methylene blue varied with target concentrations in a wide linear range from 1.0 × 10(-14)M to 1.0 × 10(-9)M with a low detection limit of 3.9 × 10(-15)M. The biosensor also showed high stability and good discrimination ability to the one-base, three-base mismatched and non-complementary sequence., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The title coordination polymer, {[Cd2(CH2N5)(C6H4NO2)Cl(OH)]·0.14H2O}n, (I), was synthesized by the reaction of cadmium acetate and N-(1H-tetrazol-5-yl)isonicotinamide in aqueous ammonia, using hydrochloric acid to adjust the pH. Under hydrothermal conditions, N-(1H-tetrazol-5-yl)isonicotinamide slowly hydrolyzes to form isonicotinic acid (Hisonic) and 5-aminotetrazole (Hatz). The deprotonated form of isonicotinic acid (denoted isonic) acts as a bridging ligand in the structure. The polymer crystallizes in the monoclinic space group C2/m. In the structure, there is one Cd3(μ3-OH) unit of Cs symmetry, with one of the Cd(II) atoms and the O and H atoms located on a mirror plane. The other crystallographically independent Cd(II) cation is located on an inversion centre. Each edge of the Cd3(μ3-OH) isosceles triangle is bridged by an atz ligand in a μ1,2 or μ2,3/μ3,4 mode. The Cd3(μ3-OH) units are laced around with a belt of chloride ligands. The belts are further connected into undulating layers via weak inter-belt Cd-Cl bonds. The two organic ligands reside across mirror planes. The construction of a three-dimensional framework is completed by the pillaring isonic ligand. Water molecules partially occupy the voids of the framework.

Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes the formation of highly toxic hydroxyl radicals, and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell-membrane-permeable iron chelators (clinically used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, the aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity after prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with the aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells and isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was nontoxic at concentrations up to its solubility limit (600 μM) and in 72-h incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is (1)H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand.

Single crystals of 4-benzoylpyridine isonicotinyl hydrazone monohydrate were grown by slow evaporation solution growth technique from ethanol at room temperature. It belongs to triclinic system with space group P1¯ and the cell parameters are, a=8.9250(2) Å, b=9.1540(2) Å, c=10.87500(10) Å and V=797.88(3) Å(3). Powder XRD closely resembles with that of simulated pattern from single crystal XRD. The characteristic functional groups present in the molecule are confirmed by FT-IR and FT-Raman analyses. The crystal is transparent in the visible region having a lower optical cut-off at ∼420 nm and the band gap energies are estimated by the application of Kubelka-Munk algorithm. Thermal analysis by TG/DTA indicates the stability of the material. The scanning electron microscopy studies reveal the surface morphology of the as-grown crystal. Mass spectrometry provides information pertaining to the structure and molecular weight of the compound. Theoretical calculations were performed using Hartree-Fock method with 6-31G(d,p) as the basis set for to derive the optimized geometry, dipole moment and first-order molecular hyperpolarizality (β) values., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Investigations into the anion effects on the molecular construction of a series of CuX₂ (X⁻ = BF₄⁻, ClO₄⁻, and NO₃⁻) complexes with 1,3,5-tris(isonicotinoyloxyethyl)cyanurate (L) were carried out. Suitable combinations of tridentate N-donor ligands and a variety of coordination geometries of copper(II) ions produce unique 1D, 2D, and 3D coordination polymers containing open cavities suitable for small chemical species, according to the nature of the polyatomic anions. Indeed, the anion exchangeability and catalytic effects of these polymers are strongly dependent on subtle anion differences, including solubility. Calcination of [Cu(ClO₄)(L)(Me₂SO)₂](ClO₄)·2CH₂Cl₂ crystals preserves its crystallinity at 200 °C, and at 600 °C finally produces stick-shaped microcrystalline copper(ii) oxide.

Seven 3-hydroxy-4-pyridinecarboxylic acid derivatives (HPs), aza-analogues of salicylic acid and structurally close to other potent inflammatory pyridine compounds such as aminopyridinylmethanols and aminopyridinamines, were synthesized, and their anti-inflammatory activity was evaluated. The synthesis was performed by adopting a general procedure involving an intramolecular Diels-Alder cycloaddition of oxazoles with acrylic acid to form various substituted pyridinic acids. The newly synthesized HPs did not exhibit cytotoxic activity on human monocytes-derived macrophages at concentrations up to 10(2) μM. Anti-inflammatory activity of the compounds was screened in vitro by evaluating the capability to inhibit cytokines release from lipopolysaccharide (LPS) stimulated human macrophages. 3-Hydroxy-1-methyl-4-pyridinecarboxylic acid (24) was found to be the most active HP. At 10 μM concentration, HP 24 reduced LPS-induced and nuclear factor-κB activation and cyclooxygenase-2 expression, while increased intracellular reactive oxygen species generation and peroxisome proliferator-activated receptor (PPAR-γ) mRNA transcript level. Indeed, pre-treatment of LPS-exposed human macrophages with PPAR-γ specific antagonist completely prevented HP 24-induced TNF-α and IL8 down regulation, demonstrating that the PPARγ pathway is mandatory for the HP 24 anti-inflammatory effect. Finally, daily treatment with HP 24 ameliorated the outcome of DSS-induced colitis in mice, significantly reducing colonic MPO activity and IL-1β tissue levels., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Complexes with silver ions have great potential for applications in medicine. Appropriate bidentate ligands, binding to silver ions, are able to generate coordination polymers as well as molecular entities as a function of ligand flexibility, conformation and length. Here we present the continuation of our previous studies in this field with ligands based on oligomers of polyethylene glycol, functionalized at both ends with either nicotinic or isonicotinic acid. The structures of three ligands and nine new coordination compounds are presented. A large variety of structures are obtained as a function of counterion, solvent and ligand-to-metal ratio, such as isolated rings, offset stacked rings, parallel chains and entangled chains, and their antimicrobial properties as well as biocompatibility are assessed.

A series of pyridines, pyrimidinones, oxazinones and their derivatives were synthesized as antimicrobial agents using citrazinic acid (2,6-dihydroxyisonicotinic acid) as a starting material. α,β-Unsaturated ketones 3a-c were condensed with cyanothio-acetamide in the presence of ammonium acetate to give 2-cyanopyridinethiones 4a-c, which were reacted with ethyl chloroacetate to yield the corresponding cyano esters 5a-c. The esters 5a-c were cyclized by action of sodium methoxide to aminoesters 6a-c, which were aminolyzed with ammonia to corresponding aminoamide derivatives 7a-c. Also, the esters 6a-c were hydrolyzed with NaOH to the corresponding sodium salt 8a-c, which were treated with acetic anhydride to afford 2-methyloxazinones 9a-c. The latter compounds were treated with ammonium acetate to afford 2-methylpyrimidinones 10a-c, followed by methylation with methyl iodide to yield 2,3-dimethyl-pyrimidinones 11a-c. The antimicrobial screening showed that many of these compounds have good antibacterial and antifungal activities comparable to streptomycin and fusidic acid used as reference drugs.

A novel, effective and simple surface-enhanced Raman scattering (SERS) nanosensor for selectively and sensitively detecting heavy metal ions in aqueous solution has been developed in the form of 2-mercaptoisonicotinic acid (2 MNA)-modified gold nanoparticles (AuNPs). Multiple heavy metal ions can be identified and quantified by using relative peak intensity ratios of selected vibrational bands in the SERS spectra of 2 MNA. Especially, concentration of Hg(2+) and Pb(2+) ions are determined by comparing the intensity ratios of the bands 1160/1230 cm(-1) for Hg(2+) and 861/815 cm(-1) (or 815/1392 cm(-1)) for Pb(2+), with detection limits of 3.4×10(-8) and 1.0×10(-7)M, respectively. 2 MNA-AuNPs sensors show a high selectivity for Hg(2+) without masking reagent, and they can also be highly selective for Pb(2+) when using sodium thiosulphate and l-cysteine as masking reagents. These results demonstrate that these 2 MNA-AuNPs nanosensors are promising candidates for in situ heavy metal ions detection and quantification, maybe even inside living cells., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The combustion of organic matter is perhaps the oldest and most common chemical transformation utilized by mankind. The generation of a C-O bond at the expense of a C-H bond during this process may be considered the most basic form of C-H functionalization. This illustrates the extreme generality of the term "C-H functionalization", because it can describe the conversion of literally any C-H bond into a C-X bond (X being anything except H). Therefore, it may be of use to distinguish between what, in our view, are two distinct categories of C-H functionalization logic: "guided" and "innate". Guided C-H functionalizations, as the name implies, are guided by external reagents or directing groups (covalently or fleetingly bound) to install new functional groups at the expense of specifically targeted C-H bonds. Conversely, innate C-H functionalizations may be broadly defined as reactions that exchange C-H bonds for new functional groups based solely on natural reactivity patterns in the absence of other directing forces. Two substrates that illustrate this distinction are dihydrojunenol and isonicotinic acid. The C-H functionalization processes of hydroxylation or arylation, respectively, can take place at multiple locations on each molecule. Innate functionalizations lead to substitution patterns that are dictated by the inherent bias (steric or electronic) of the substrate undergoing C-H cleavage, whereas guided functionalizations lead to substitution patterns that are controlled by external directing forces such as metal complexation or steric bias of the reagent. Although the distinction between guided and innate C-H functionalizations may not always be clear in cases that do not fit neatly into a single category, it is a useful convention to consider when analyzing reactivity patterns and strategies for synthesis. We must emphasize that although a completely rigorous distinction between guided and innate C-H functionalization may not be practical, we have nonetheless found it to be a useful tool at the planning stage of synthesis. In this Account, we trace our own studies in the area of C-H functionalization in synthesis through the lens of "guided" and "innate" descriptors. We show how harnessing innate reactivity can be beneficial for achieving unique bond constructions between heterocycles and carbonyl compounds, enabling rapid and scalable total syntheses. Guided and innate functionalizations were used synergistically to create an entire family of terpenes in a controlled fashion. We continue with a discussion of the synthesis of complex alkaloids with high nitrogen content, which required the invention of a uniquely chemoselective innate C-H functionalization protocol. These findings led us to develop a series of innate C-H functionalization reactions for forging C-C bonds of interest to the largest body of practicing organic chemists: medicinal chemists. Strategic use of C-H functionalization logic can have a dramatically positive effect on the efficiency of synthesis, whether guided or innate.

A tale of two polyhedra: two nested Archimedean metal-organic polyhedra, a rhombicuboctahedron (Co(48) cage) and a cuboctahedron (Co(24) cage), have been assembled from two types of cobalt dimers and two complementary ligands. Within the 3D covalent cubic array of outer Co(48) cages and framework lie encapsulated inner Co(24) cages that are linked into a separate "hidden" 3D framework., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The increase in the prevalence of drug-resistant tuberculosis cases demonstrates the need of discovering new and promising compounds with antimycobacterial activity. As a continuation of our research and with the aim of identifying new antitubercular drugs candidates, a new series of quinoxaline 1,4-di-N-oxide derivatives containing isoniazid was synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Moreover, various drug-like properties of new compounds were predicted. Taking into account the biological results and the promising drug-likeness profile of these compounds, make them valid leads for further experimental research., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form π-stacking interactions with the catalytic Tyr24 have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19-24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.

(Arene)dichloridoruthenium(II) complexes with N-coordinated isonicotinates of androgens (6) and estrogens (9) were prepared and tested for affinity to the estrogen receptor (ERα) and sex hormone binding globulin (SHBG), as well as for cytotoxicity in cancer cells. None of the new complexes bound noticeably to the ER and most of them also bound less strongly to SHBG than the corresponding unmetallated steroids 7. In MTT assays the Ru(p-cymene) complexes 9 of 2-substituted estrones were equally or even more cytotoxic than the metal-free steroids against hormone-dependent (MCF-7 breast and KB-V1 cervix carcinomas) and hormone-independent (518A2 melanoma) cells. The addition of external SHBG to MTT assays lowered the cytotoxicities of the complexes 9 and distinctly more so those of some steroids 7, probably by the way of sequestration and reduction of the cellular uptake. In the absence of SHBG the estrogen complexes 9 were internalized by 518A2 melanoma cells and ruthenated their DNA as quantified by ICP-OES. They also ruthenated salmon sperm DNA but did not change the topology of plasmid DNA in EMSA experiments. In addition, the Ru(p-cymene) complex of 2-ethoxyestrone (9c) was shown to reduce the motility of 518A2 melanoma cells in a wound-healing assay., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Current approaches to the treatment of herpes infection, particularly Epstein-Barr virus (EBV), include the use of etiotropic medicines, as well as sensitizing therapy. This virus plays an important role in the etiology of nasopharyngeal carcinoma, adenocarcinoma of the parotid glands, gastric carcinoma, Burkitt's lymphoma and lymphoproliferative syndromes [1, 2, 3]. The spectrum of drugs active against EBV remains very limited, and gancyclovir and acyclovir are used in medical practice, so the search of new compounds active against EBV remains urgent. The purpose of this work was to study antiEBV activity of isonicotinic acid derivatives in the cultures of lymphoblastoid Raji cells, B95-8, Namalwa. The indices of cytotoxicity (CC50) which amounted to 840, 1250 and 3000 microg/ml and the concentration of drugs, which inhibit the virus (IC50) reproduction is 0.1, 2.5 and 50 microg/ml, respectively, in cell cultures were identified. It was detected, the drug 4-(n-benzyl)aminocarbonyl-1-methylpyridinium iodide (PV-1) had an ability to inhibit reproduction of the Epstein-Barr virus in all studied cells cultures. The compounds PV-2 and PV-10 were less toxic in respect of the initial preparation PV-1, but their antiviral activity was manifested at 25 and 500 times higher concentrations. It, respectively, influenced the decrease of their selectivity index, which was 8400 for PV-1, 400 and 440--for PV-2 and PV-10. These studies suggest possible ways of further modification of the PV-1 molecule to create highly specific inhibitors of Epstein-Barr virus. The paper is presented in Ukrainian.

The in situ formed hydrazone Schiff base ligand (E)-N'-(2-hydroxy-3-methoxybenzylidene)benzoylhydrazone (H₂L¹) reacts with copper(II) acetate in ethanol in the presence of pyridine-4-carboxylic acid (isonicotinic acid, HL²) to green-[Cu(HL¹)(L²)]·H₂O·C₂H₅OH (1) and brown-[Cu(L¹)(HL²)] (2) complexes which crystallize as concomitant tautomers where either the mono-anion (HL¹)⁻ or di-anion (L¹)²⁻ of the Schiff base and simultaneously the pyridine-carboxylate (L²)⁻ or the acid (HL²) (both through the pyridine nitrogen atom) function as ligands. The square-planar molecular copper(II) complexes differ in only a localized proton position either on the amide nitrogen of the hydrazone Schiff base in 1 or on the carboxyl group of the isonicotin ligand in 2. The proportion of the tautomeric forms in the crystalline solid-state can be controlled over a wide range from 1:2 = 95 : 5 to ∼2 : 98 by increasing the solution concentration. UV/Vis spectral studies show both tautomers to be kinetically stable (inert), that is, with no apparent tautomerization, in acetonitrile solution. The UB3LYP/6-31+G* level optimized structures of the two complexes are in close agreement with experimental findings. The solid-state structures feature 1D hydrogen-bonded chain from charge-assisted O((-))H-N and O-H((-))N hydrogen bonding in 1 and 2, respectively. In 1 pyridine-4-carboxylate also assumes a metal-bridging action by coordinating a weakly bound carboxylate group as a fifth ligand to a Cu axial site. Neighboring chains in 1 and 2 are connected by strong π-stacking interactions involving also the five- and six-membered, presumably metalloaromatic Cu-chelate rings.

Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD)., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.

Several 2-amino-4-carboxypyridine, 4- and 5-carboxypyridone-based compounds were prepared and tested against three members of the chorismate-utilising enzyme family, anthranilate synthase, isochorismate synthase and salicylate synthase. Most compounds exhibited low micromolar inhibition of these three enzymes. The most potent inhibitor was a 4-carboxypyridone analogue bearing a lactate side chain on the pyridyl nitrogen which exhibited inhibition constants of 5, 91 and 54 muM against anthranilate synthase, isochorismate synthase and salicylate synthase respectively.