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Enzymatic conversion of nitriles to carboxylic acids by nitrilases has gained significance in the green synthesis of several pharmaceutical precursors and fine chemicals. Although nitrilases from several sources have been characterized, there exists a scope for identifying broad spectrum nitrilases exhibiting higher substrate tolerance and better thermostability to develop industrially relevant biocatalytic processes. Through genome mining, we have identified nine novel nitrilase sequences from bacteria and evaluated their activity on a broad spectrum of 23 industrially relevant nitrile substrates. Nitrilases from Zobellia galactanivorans, Achromobacter insolitus and Cupriavidus necator were highly active on varying classes of nitriles and applied as whole cell biocatalysts in lab scale processes. Z. galactanivorans nitrilase could convert 4-cyanopyridine to achieve yields of 1.79 M isonicotinic acid within 3 h via fed-batch substrate addition. The nitrilase from A. insolitus could hydrolyze 630 mM iminodiacetonitrile at a fast rate, effecting 86 % conversion to iminodiacetic acid within 1 h. The arylaliphatic nitrilase from C. necator catalysed enantioselective hydrolysis of 740 mM mandelonitrile to (R)-mandelic acid in 4 h. Significantly high product yields suggest that these enzymes would be promising additions to the suite of nitrilases for upscale biocatalytic application.

Novel isonicotinic acid hydrazide functionalized silver nanoparticles (INH-AgNPs) were synthesized by wet chemical method and used for the detection of Hg2+ ions in aqueous medium. The INH-AgNPs exhibit good absorbance and emission peaks by sensing Hg2+ ions with visible color changes. The detection of Hg2+ ions was confirmed by FT-IR, EDAX spectra and by the changing morphology of INH-AgNPs, and after addition of Hg2+ was confirmed by SEM and TEM imaging studies. Based on the emission intensity the probe INH-AgNPs exhibit a lowest detection limit (LOD) of Hg2+ to 0.18 nM. The association constant (Ka) of INH-AgNPs + Hg2+ ions is calculated using the Bensei-Hildebrand equation. Also, the probe is successfully utilized for the detection of Hg2+ ions in real water samples obtained from different fields, which showed good results.

Luminescent complexes illustrate high interest as luminescent materials in the fields of optical communications, lighting, sensors and biomedical devices. This review gives the structural and luminescent studies on isonicotinic acid based complexes, and probably provides the structure-property relationship. These complexes display various luminescent properties, such as luminescent probe, different luminescence when immersed in different organic solvents. This review is divided into three sections to discuss, including transition-metal, lanthanide, lanthanide-transition heterometal. The approach will help design and synthesis of luminescent complexes as promising materials.

The first examples of adenine binding by isomeric organoplatinum(II) complexes bearing H-bonding nicotinic and isonicotinic acid ligands are reported. Notably, a subtle switching of the H-bonding functionality from the 3- to 4-position of the pyridyl ring leads to a significant change in both the strength of association and the site of adenine binding. Australian Research Council (ARC)

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 A. OWS is a newly discovered KDM4D inhibitor (IC50 = 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.

Discrimination of active pharmaceutical ingredients (APIs) existing as neutral molecules or salts is essential and complicated. However, the discrimination of pharmaceutical salts by confocal Raman micro-spectroscopy remains relatively poorly understood. In this paper, four new salts of triamterene (Tri) cocrystallized with nicotinic acid (NA), benzoic acid (BA), p-toluenesulfonic acid (TA), or isonicotinic acid (INA) were prepared and characterized comprehensively by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), and dynamic vapor sorption (DVS). Ionized pteridine is identified by marker peaks in the confocal Raman micro-spectra that are characteristic of C[double bond, length as m-dash]N. The single crystal structures of Tri-NA·H2O and Tri-TA further demonstrate that a proton transfers from the carboxylic group of NA or TA to the pyrimidine N1 atom of Tri and their salts formation take place. The intrinsic dissolution rate (IDR) and apparent equilibrium solubility of these four salts are improved compared to the pure Tri component, especially for Tri-BA. This study provides a valuable insight into pharmaceutical salt discrimination by vibrational spectroscopy and presents that the combination of Tri with an acid can be a possible and promising alternative formulation of Tri.

Currently, analytical scientists are paying special attention to reducing reliance on hazardous chemicals in various analytical methods. By embracing this concept, we developed an eco-friendly high-performancethin-layer chromatography (HPTLC) method as an alternative for the conventional HPLC method for the determination of an essential human micronutrient, niacin (NIA), which is used improve the lipid profile of patients. Furthermore, the proposed HPTLC method is capable of determining the structurally related impurities of NIA such as pyridine-2,5-dicarboxylic acid, isonicotinic acid, pyridine, and 5-ethyl-2-methylpyridine, which exhibit nephrotoxic and hepatotoxic effects. The separation of this challenging mixture was achieved on HPTLC sheets using a mixture of ethyl acetate/ethanol/ammonia solution (6:4:0.05, v/v/v), and then the dried plates were scanned at 254 nm. The analytical eco-scale assessment protocol was used to assess the greenness profile of the presented method and compare it with the reported HPLC method. The suggested method was found to be greener with regard to the consumption of solvents and the yielding of waste. The results suggest that the described method can be safely implemented for the routine analysis of NIA pharmaceutical dosage without the interference of potential impurities in quality control laboratories.

By virtue of combining an in-situ assembly process with a stepwise synthesis in conventional aqueous solution, two series of unique organic-inorganic hybrid heteropolyoxomolybdates were constructed from plenary Keggin germanomolybdates and Cu-Ln heterometallic units and fully characterized: [H2 INA]2 H8 [LnCu(INA)4 (H2 O)6 ]2 [α-GeMo12 O40 ]3 ⋅52 H2 O (Ln=La3+ (1), Ce3+ (2), Pr3+ (3), Nd3+ (4), Sm3+ (5), Eu3+ (6); HINA=isonicotinic acid) and (NH4 )[Cu(PA)2 ][Cu(PA)2 Ln(H2 O)8 ][α-GeMo12 O40 ]⋅10 H2 O (Ln=Nd3+ (7), Sm3+ (8), Eu3+ (9); HPA=picolinic acid). The most remarkable structural characteristic of compounds 1-6 was that their molecular units were defined by three discrete plenary Keggin [α-GeMo12 O40 ]4- polyoxoanions and two organic-inorganic hybrid heterometallic [LnCu(INA)4 (H2 O)6 ]+ moieties, whereas compounds 7-9 exhibited a nice-looking 1D chain-like structure that was built from plenary [α-GeMo12 O40 ]4- polyoxoanions, pendent [Cu(PA)2 ] complexes, and bridging {[Cu(PA)2 ][Ln(H2 O)8 ]}3+ heterometallic groups. Notably, two different pyridine carboxylic acid ligands led to the discrepancy between the two structure types. To the best of our knowledge, compounds 1-9 constitute the first examples of plenary Keggin heterometallic germanomolybdates that include Cu-Ln-organic subunits. Further studies revealed that compounds 3 and 8 exhibited fast adsorption capacity for cationic dyes methylene blue (MB) and rhodamine B (RhB) in water. Moreover, compounds 3 and 8 could quickly and selectively adsorb MB from a mixture of MB/methyl orange (MO) or MB/azophloxine (Apo).

New pyridine derivatives were designed and synthesized as Isonicotinic acid hydrazide (INH) analogues. The synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis strain H37Rv. Ten compounds (3c, 3e-g, 5a-c, 6h, 10 and 11b) showed promising antitubercular activity with MIC range 7.30 µM–19.39 µM. Compounds 3e, 3g, 5b and 11b were the most potent analogues, with MIC 7.30–8.74 µM. They were equipotent to the standard drug Ethambutol (MIC 7.64 µM) and more active than the standard drug Pyrazinamide (MIC 50.77 µM). They were further examined for cytotoxicity in human embryonic kidney (HEK) cell line at the concentration of 50 µg/mL using MTT assay. Results declared that most compounds showed acceptable safety margin. Molecular Docking studies into 2-trans-enoyl-acyl carrier protein reductase, called InhA have been conducted for compounds 3e, 3g, 5b and 11b using Molecular Operating Enviroment software (MOE 2016.0802), where reasonable binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration and Osiris software.

Trifluoromethylation of isonicotinic acid hydrazide has been investigated in trifluoroacetic acid containing pyridine, triethylamine and sodium trifluoroacetate dissolved in acetonitrile on platinum and glassy carbon electrodes using cyclic voltammetry. LSVs for isonicotinic acid hydrazide in 0.1 M TFA/ Py/TEA/NaTFA in acetonitrile on platinum electrode show that there is no distinct oxidation peak for the oxidation of isonicotinicacid hydrazide within the voltammetric region of 0.0 to 1.6 V vs Ag and it gets oxidized anodically in the gas evolution region itself. TFA/ NaTFA medium shows slightly higher current density than the other two media for the oxidation of isonicotinic acid hydrazide. CVs for different concentrations of isonicotinic acid hydrazide show that anodic peak becomes broad and flat. It shows that severe adsorption of INAH/product takes place on the glassy carbon electrode during the voltammetry scanning. Galvanostatic electrolysis of INAH in TFA/Py/ACN medium at low current density on Pt shows good conversion with low selectivity.

The problem of designing new antitubercular drugs against multiple drug‐resistant tuberculosis (MDR‐TB) was addressed using advanced machine learning methods. As there are only few published measurements against MDR‐TB, we collected a large literature data set and developed models against the non‐resistant H37Rv strain. The predictive accuracy of these models had a coefficient of determination q2=.7–.8 (regression models) and balanced accuracies of about 80% (classification models) with cross‐validation and independent test sets. The models were applied to screen a virtual chemical library, which was designed to have MDR‐TB activity. The seven most promising compounds were identified, synthesized and tested. All of them showed activity against the H37Rv strain, and three molecules demonstrated activity against the MDR‐TB strain. The docking analysis indicated that the discovered molecules could bind enoyl reductase, InhA, which is required in mycobacterial cell wall development. The models are freely available online (http://ochem.eu/article/103868) and can be used to predict potential anti‐TB activity of new chemicals.

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.

Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.

In this work, the group contribution method of Chickos et al. was applied to estimate the fusion enthalpy of isonicotinic acid, and the obtained result (29.2 kJ·mol − 1 ) showed a large difference with the value (135 kJ·mol − 1 ) as reported from literatures and as determined by differential scanning calorimetry (DSC). The results of DSC/TG measurement showed that the phase transition of isonicotinic acid from 187.27 °C to 277.47 °C underwent a sublimation process, with a sublimation enthalpy of 128.03 kJ·mol − 1 . An efficient analytical technique combining pyrolysis and gas chromatography/mass spectrometry (Py-GC/MS) was used to prove this conclusion.

Two novel two-dimensional Ln coordination polymers (CPs) [Ln3 (μ3-OH)(IN)3(HIDA) (IDA)2]n (Ln = Eu, 1; Sm, 2; HIN = isonicotinic acid, and H2IDA = iminodiacetic acid) have been successfully synthesized under solvothermal conditions and characterized by IR, TG, and elemental analyses. The structures of 1 and 2 were determined by single-crystal X-ray structural analysis, which shows that LnIII ions interconnect through HIN and H2IDA molecules to generate a 1D chain, and the adjacent chains are joined together by the same form to form the 2D zonary plane of 1 and 2. Meanwhile, We also studied luminescence properties of 1 and 2. The luminescence lifetime and quantum yield of 1 are 1.32 ms and 25.30%, which are significantly longer and higher than the values obtained for reported Eu3+ coordination polymers in the solid state at room temperature.

Remodeling of the extracellular matrix of the liver in mice with BCG-induced granulomatosis after 2-month course of intraperitoneal injections of isonicotinic acid hydrazide, oxidized dextran conjugated with isonicotinic acid hydrazide, dextrazide, and its liposome-encapsulated form manifested in modification of the proteoglycan composition and hydroxyproline fractions associated with changes in hyaluronidase and MMP activities. The antifibrotic effect of dextrazide and its liposome-encapsulated form manifested in reduction of hydroxyproline fractions that reflected the process of collagen synthesis. Administration of isonicotinic acid hydrazide was followed by a decrease in hydroxyproline fractions reflecting collagen synthesis (antifibrotics effect) and degradation (profibrotic effect), which can be explained by its hepatotoxic activity.

Thirteen new 3-acetyl-2,5-disubstituted-1,3,4-oxadiazoline derivatives were synthesized from corresponding hydrazide-hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, 1 H-NMR, 13 C-NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4-oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.

Amide-functionalized metal-organic frameworks (AFMOFs) as a subclass of MOF materials have received great interest recently because of their intriguing structures and diverse potential applications. In this work, solvothermal reactions between indium nitrate and two mixed-linkers afforded two new isoreticular 8-connected trinuclear indium-based AFMOFs of [(In3 O)(OH)(L2)2 (IN)2 ]⋅(solv)x (2-In) and [(In3 O)(OH)(L2)2 (AIN)2 ]⋅(solv)x (NH2 -2-In) (H2 L2=4,4'-(carbonylimino)dibenzoic acid and HIN=isonicotinic acid or HAIN=3-aminoisonicotinic acid), respectively. Moreover, by means of reticular chemistry, an extended network of [(In3 O)(OH)(L3)2 (PB)2 ]⋅(solv)x (3-In) (H2 L3=4,4'-(terephthaloylbis(azanediyl))dibenzoic acid, HPB=4-(4-pyridyl)benzoic acid) was also successfully realized after prolongation of the former dicarboxylate linker and HIN, resulting in a truly 8-connected isoreticular AFMOF platform. These frameworks were structurally determined by single-crystal X-ray diffraction (SCXRD). Sorption studies further demonstrate that 2-In and NH2 -2-In exhibit not only high surface areas and pore volumes but also relatively high carbon capture capabilities (the CO2 uptakes reach 60.0 and 75.5 cm3 g-1 at 298 K and 760 torr, respectively) due to the presences of amide and/or amine functional groups. The selectivity of CO2 /N2 and CO2 /CH4 calculated by IAST are 10.18 and 12.43, 4.20 and 4.23 for 2-In and NH2 -2-In, respectively, which were additionally evaluated by mixed-gases dynamic breakthrough experiments. In addition, high-pressure gas sorption measurements show that both materials could take up moderate amounts of natural gas.

It was previously reported that 6β-aminomorphinan derivatives show high affinity for opiate receptors. Novel 6β-heteroarylamidomorphinanes were designed based on the MOR selective antagonist NAP. The 6β-aminomorphinanes were prepared by stereoselective Mitsunobu reaction and subsequently acylated with nicotinic acid and isonicotinic acid chloride hydrochlorides. The receptor binding and efficacy were determined in vitro and the analgesic activity was studied in vivo. The in vitro studies revealed moderate selectivity for the MOR. At least two compounds in this series exhibited a long-lasting analgesic response when administered subcutaneously and intracerebroventricularly. When the substances were given intracerebroventricularly to mice, they showed analgesic potency comparable to morphine.

An unreported inorganic–organic hybrid compound [{Cu2(phen)2(ina)2(H2O)}{Cu(phen)2}(H2P2W18O62)]·10H2O(1) (phen = 1,10-phenanthroline, ina = isonicotinate anion) was hydrothermally synthesized and characterized with elemental analysis, IR spectroscopy, thermal analysis, luminescent spectroscopy, UV/Vis diffuse reflection spectroscopy, magnetic measurement. The crystal structure was determined with X-ray single-crystal diffraction. [Cu(phen)2]2+and [Cu2(phen)2(ina)2(H2O)]2+ units are grafted on the Dawson anion [P2W18O62]6− via the terminal oxygen atoms of two WO6 octahedra. In [Cu2(phen)2(ina)2(H2O)]2+ unit Cu2+ ions displays a square-pyramidal geometry, and in [Cu(phen)2]2+ unit the geometry of Cu2+ ion is more close to triangle bipyramidal geometry including a terminal oxygen atom. Hydrogen bonds exist between the decorated Dawson anions and water molecules. The compound 1 has a narrow band gap of 2.05 eV and strong emission at 437 nm. Variable-temperature magnetic measurement of 1 shows a typical antiferromagnetic interaction in the 2–300 K temperature range.

The synthesis of N-[dimethoxyphosphoryl-(3,5-di-tert-butyl-4-hydroxyphenyl)] methylisatins has been performed by the addition of isatin and 5-butylisatin to the double bond of dimethyl-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)methylphosphonate. Subsequent functionalization of the compounds synthesized with thiosemicarbazide hydrochloride, 3-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)propionic acid hydrazide, and isonicotinic acid. Hydrazide gave isatin derivatives containing several pharmacophore fragments. Each of them has the ability to the increase the antioxidant and biological activities of these compounds.

A novel zinc porphyrin ZnP bearing a 1,3,5-triazine-2,4-diamine unit has been designed and synthesized in good yields to construct axial-coordinated assemblies (denoted as ZnP–Ai, i = 1, 2, 3 and 4) with different isonicotinic acid analogues (assigned as A1, A2, A3 and A4) through zinc-to-ligand axial coordination approach. Then these assemblies were grafted onto TiO2 electrode surface to build dye sensitized solar cells. The performance of these cells also was examined. Photoelectrochemical measurements illustrate that all the assembly based cells have certain capabilities to export photocurrent. Especially, the ZnP–A2 assembly with a cyanoacrylic acid group based solar cell has the highest conversion efficiency of 0.81% with a JSC of 3.0 mA/cm2, a VOC of 0.38 V, and a FF of 0.71 among these assembly based solar cells. Additionally, the UV–vis absorption, fluorescence spectra, density functional theory (DFT) calculations, transmission electron microscopy (TEM) and electrochemical impedance spectra (EIS) were performed to determine the photoelectric behavior as well as morphological structure on the TiO2 surface modified by these assemblies.

Arene ruthenium complexes containing long-chain N-ligands L1 = NC5H4–4-COO–C6H4–4-O–(CH2)9–CH3 or L2 = NC5H4–4-COO–(CH2)10–O–C6H4–4-COO–C6H4–4-C6H4–4-CN derived from isonicotinic acid, of the type [(arene)Ru(L)Cl2] (arene = C6H6, L = L1: 1; arene = p-MeC6H4Pr i , L = L1: 2; arene = C6Me6, L = L1: 3; arene = C6H6, L = L2: 4; arene = p-MeC6H4Pr i , L = L2: 5; arene = C6Me6, L = L2: 6) have been synthesized from the corresponding [(arene)RuCl2]2 precursor with the long-chain N-ligand L in dichloromethane. Ruthenium nanoparticles stabilized by L1 have been prepared by the solvent-free reduction of 1 with hydrogen or by reducing [(arene)Ru(H2O)3]SO4 in ethanol in the presence of L1 with hydrogen. These complexes and nanoparticles show a high anticancer activity towards human ovarian cell lines, the highest cytotoxicity being obtained for complex 2 (IC50 = 2 μM for A2780 and 7 μM for A2780cisR).

The obstructive renal radioactivity after injection of antibody fragments/constructs labeled with metallic radionuclides would be improved by liberating a radiometal chelate of urinary excretion from the antibody molecules by enzymes on the renal brush border membrane (BBM). A tripeptide GFK sequence was newly evaluated as an enzyme-cleavable linkage and conjugated to a 99mTc chelate of an isonicotinic acid derivative of 2-picolylglycine (99mTc-IPG). 99mTc-IPG-glycine was liberated from 99mTc-IPG-GFK by the enzymes, while 99mTc-IPG-GK (where the tripeptide GFK was substituted with a dipeptide GK) did not. When injected into mice, 99mTc-IPG-GFK-conjugated Fab exhibited lower renal radioactivity levels than directly radioiodinated Fab shortly after injection without reducing the tumor radioactivity levels, due to a release and excretion of 99mTc-IPG-glycine by enzymes present on the renal BBM. These findings would provide insights to develop antibody fragments/constructs labeled with metallic radionuclides ...

The oxidation of an antitubercular drug isoniazid by a lipopathic oxidant cetyltrimethylammonium dichromate (CTADC) in a nonpolar medium generates isonicotinic acid both in the presence and the absence of acetic acid. The conventional UV–vis spectrophotometric method is used to study the reaction kinetics. The occurrence of the Michaelis–Menten–type kinetics with respect to isoniazid confirms the binding of oxidant and substrate to form a complex before the rate-determining step. The existence of the inverse solvent kinetic isotope effect, k(H2O)/ k(D2O) = 0.7, in an acid-catalyzed reaction proposes a multistep reaction mechanism. A decrease in the rate constant with an increase in [CTADC] reveals the formation of reverse micellar–type aggregates of CTADC in nonpolar solvents. In the presence of different ionic and nonionic surfactants, CTADC forms mixed aggregates and controls the reaction due to the charge on the interface and also due to partition of oxidant and substrate in two different domains. High negative entropy of activation (ΔS‡ = –145 and –159 J K−1 mol−1 in the absence and presence of acetic acid) proposes a more ordered and highly solvated transition state than the reactants. Furthermore, the solvent polarity-reactivity relationship reveals (i) the presence of less polar and less ionic transition state compared to the reactants during the oxidation, (ii) differential contribution from nonpolar and dipolar aprotic solvents toward the reaction process, and (iii) the existence of polarity/hydrophobic switch at log P = 0.73. A suitable mechanism has been proposed on the basis of experimental results. These results may provide insight into the mechanism of isoniazid oxidation in hydrophobic environment and may assist in understanding the drug resistance in different location.

The biotransformation of isonicotinamide was investigated using thermophilic intracellular amidase produced from Geobacillus subterraneus RL-2a. Various process parameters, including amount of biocatalyst, substrate feeding rate, enzyme-to-substrate ratio and operational thermostability were systematically examined with the aim of achieving complete substrate conversion and high productivity. In 1 L fed batch reaction containing 0.1 M isonicotinamide, in 0.2 M potassium phosphate buffer (pH 6.5, 200 rpm) and 8 U ml −1 amidase activity (12.48 mg dcw ml −1 ) of whole cells of G. subterraneus RL-2a (as biocatalyst) resulted in a yield of 0.1 M of isonicotinic acid after 50 min reaction time at 70 °C and a total of 61.55 g isonicotinic acid was produced at a rate of 1.18 g h −1 g −1 dcw respectively. The volumetric productivity was 14.8 g h −1 l −1 .

The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intra-molecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

Three new complexes of the [Re6(μ3-Se)8]2+ core-containing cluster with isonicotinic acid (INA) were synthesized and characterized by multinuclear NMR (1H and 31P) and high-resolution mass spectrometry. Their molecular and crystal structures were determined by single-crystal X-ray diffraction studies. Unusual degrees of deprotonation of the INA ligand(s) are observed in the crystal structure, possibly due to the activation by the Lewis acidic cluster core. Extensive hydrogen bonding interactions occurring between carboxylate groups of neighboring cluster units as revealed by crystallographic studies lead to the assembly of both linear and zigzag multi-cluster chains in the solid state.

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.

Enoyl–acyl carrier protein reductase (InhA) is an important enzyme for the biosynthesis of mycolic acids which are central constituents of the mycobacterium cell wall. In the present study, we synthesized, characterized hydrophobic N-acylated isonicotinic acid hydrazide derivatives (2a–2m) as potential enoyl–acyl carrier protein reductase (InhA) inhibitors and tested them against Mycobacterium tuberculosis H37Rv and two human clinical isolates by means of colorimetric tetrazolium micro-plate assay. Compounds 2c–2m displayed good-to-excellent inhibitory activity against all tested strains as compared with isoniazid. In vivo acute toxicity studies were performed by Up-and-Down procedure. The results showed that all the tested compounds were non-toxic and well tolerated considering their LD50 values ranging from 3,898 to 5,000 mg/kg body weight.

Two new self-assemblies based on two zinc porphyrins substituted at the meso-positions with different donor units (denoted as ZnP1 and ZnP2) and isonicotinic acid (A) by metal-ligand axial coordination have been designed and immobilized on the double-layer nanostructured TiO2 film-coated highly transparent FTO conducting glass electrode in a photosynthesis device. These cells were also measured under irradiance of 100 mW cm(-2) AM 1.5G sunlight. The results reveal that the performance of ZnP2-A outperforms that of ZnP1-A. The UV-vis absorption spectra, fluorescence spectra, molecular orbital (MO) patterns, and HOMO-LUMO energy gaps of these assemblies were also investigated to further demonstrate the photovoltaic behavior of these cells. (C) 2013 Elsevier Ltd. All rights reserved.

1,1′-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When 14C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration-dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant ( Ki) value of 66.6 µmol/L. Based on the kinact/ KI values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein.

The transformation dynamics of 2- and 4-cyanopyridines by cells suspended and adsorbed on inorganic carriers has been studied in the Rhodococcus ruber gt1 possessing nitrile hydratase activity and the Pseudomonas fluorescens C2 containing nitrilase. It was shown that both nitrile hydratase and nitrilase activities of immobilized cells against 2-cyanopyridine were 1.5–4 times lower compared to 4-cyanopyridine and 1.6–2 times lower than the activities of free cells against 2-cyanpopyridine. The possibility of obtaining isonicotinic acid during the combined conversion of 4-cyanopyridine by a mixed suspension of R. ruber gt1 cells with a high level of nitrile hydratase activity and R. erythropolis 11-2 cells with a pronounced activity of amidase has been shown. Immobilization of Rhodococcus cells on raw coal and Pseudomonas cells on kaolin was shown to yield a heterogeneous biocatalyst for the efficient transformation of cyanopyridines into respective amides and carboxylic acids.

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.

Isoniazid is one of the widely used first-line drugs in the treatment of tuberculosis for many years but the mechanism of the action of the drugs is still not clear. Herein, we report the synthesis, QSAR model study and biological effects of esters and thioester derivative of isonicotinic acid (INA) on different strains of Mycobacterium tuberculosis in an attempt to establish the mode of action of the active form of Isoniazid (INH). The esters of INA are expected to show antibiotic activities against strains of Mycobacterium tuberculosisupon activation by intracellular nonspecific esterases, while thioesters is expected not to show antimicrobial effects and thus served as control. The obtained results indicated that the synthesized esters did not show antimicrobial activity. The conclusion drawn from the result is that either INA is not the active form of INH or that the esters show poor water solubility- in addition to the possibility of acquired during resistance of the strains during culture and testing - all of which could hamper mycobacterial cell up take. This suggests that more studies are needed to search for the possible active form of isoniazid.

Lutein a hydroxy carotenoid belonging to xanthophyll group having a hydroxylgroup attached to either end of the molecule, making it react more strongly with singlet oxygen than other carotenoids. In the present study, Lutein was modified by appending pyridine moiety for increased antioxidant activity and its ability to inhibit H2O2 induced TGF-β1 expression in peripheral blood mononuclear cells was investigated. Lutein was treated with Isonicotinic acid (Pyridine-4-carboxylic acid) in thepresence of DCC and DMF as solvent medium to obtain pyridine appended Lutein (2.28mg/ml). The pyridine appended Lutein was purified using silica gel-G (60–120mesh) column, further by HPLC and fractions were eluted at the rate of 1ml/min using water, acetonitrile, methanol and dichloromethane as mobile phase in the ratio 0.5:9.5:67.5:22.5. A major peak was obtained at 454nm with retention time of 1.60min. In dose dependent study, Pyridine appended Lutein at 0.42µmoles showed a maximum of 91.6% of DPPH radical scavenging activity in comparison to unmodified Lutein (80.76%). Unmodified Lutein showed maximum activity (86.18% at 1.25µmoles) with 2.97 folds higher than Pyridine appended Lutein. TGF–β1 expression in H2O2 (3mM) treated peripheral blood mononuclear cells was inhibited by 83.14% (152.1pg/ml) and 76.21% (214.62pg/ml) at 0.92µmoles of Pyridine appended Lutein and unmodified Lutein respectively compared to H2O2 treated cells (902.15pg/ml) without test samples. In conclusion, Pyridine appended Lutein showed higher DPPH radical scavenging activity and inhibited H2O2 induced TGF–β1 expression in peripheral blood mononuclear cells at low concentrations than unmodified Lutein.

An alternative methodology for simultaneous determination of isoniazid, isonicotinic acid, 4-cyanopyridine, ethyl isonicotinate and isonicotinamide by capillary zone electrophoresis, within an analysis time of 11 min, is proposed. An electrolyte composed by 50 mmol L−1 of acetic acid/sodium acetate buffer and 12.5 mmol L−1 of Cu2+, an analyte dilution in 1 mmol L−1 of Brij 35 and 12.5 mmol L−1 of Cu2+ and +20 kV voltage were optimized. After evaluating some figures of merit, such as linearity, precision, recovery and quantification limit, the method was successfully applied to the isoniazid analysis in tablets. The contents found were 99.3 mg of isoniazid and 0.3 mg of isonicotinic acid, corresponding to 0.3 % of impurity regarding the content of the active ingredient in the pharmaceutical formulation.

Two proton-conductive molecular hybrids were constructed by introducing protonated water clusters, alkaline-earth metal ions and [PMo12O40]3− anions in the gallery of H-bonding networks based on isonicotinic acid N-oxide. Single-crystal X-ray diffraction analyses at 293 K revealed that two complexes crystallized in the orthorhombic space group Pnnm, exhibited very close unit cell parameters, and presented similar three-dimensional hydrogen-bonded networks with large one-dimensional (1D) channels. Interestingly, typical or decorated poly-Keggin-anion chains are formed in the 1D channels. Surprisingly, the proton conductivities of two complexes in the temperature range of 85–100 °C under 98% RH conditions reached good proton conductivities of 10−3 S cm−1. A possible mechanism of the proton conduction was proposed according to the experimental results.

Dihydroorotate dehydrogenase (DHODH) is a central enzyme of pyrimidine biosynthesis which catalyzes oxidation of dihydroorotate (DHO) to orotate (ORO). DHODH inhibitors are considered as promising targets for the development of antiproliferative, antiparasitic, and immunosuppressive drugs. The best 2D QSAR model for the prediction of human dihydroorotate dehydrogenase (hDHODH) inhibitory activity was obtained by applying MLR giving r2 = 0.834 and q2 = 0.756, PCR giving r2 = 0.833 and q2 = 0.756, and PLS giving r2 = 0.864 and q2 = 0.786. 2D QSAR studies reveal the importance of alignment independent descriptors for predicting hDHODH inhibitory activity. The 3D QSAR study was performed by comparative molecular field analysis (CoMFA) to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The best CoMFA model obtained for the training set was statistically significant with cross-validated coefficients (q2) of 0.630 and conventional coefficients (r2) of 0.949. The CoMFA contour maps suggest some important structural features-like electronegative substituents at biphenyl ring system for strong inhibitory activity. We believe that these results are helpful in design of more potent and selective hDHODH inhibitors.

For over a decade, tuberculosis (TB) has been the leading cause of death among infectious diseases. Since the 1950s, isoniazid has been used as a front-line drug in the treatment of TB; however, resistant TB strains have limited its use. The major route of isoniazid resistance relies on KatG enzyme disruption, which does not promote an electron transfer reaction. Here, we investigated the reactivity of isoniazid metal complexes as prototypes for novel self-activating metallodrugs against TB with the aim to overcome resistance. Reactivity studies were conducted with hydrogen peroxide, hexacyanoferrate(III), and aquopentacyanoferrate(III). The latter species showed a preference for the inner-sphere electron transfer reaction pathway. Additionally, electron transfer reaction performed with either free isoniazid or (isoniazid)pentacyanoferrate(II) complex resulted in similar oxidized isoniazid derivatives as observed when the KatG enzyme was used. However, upon metal coordination, a significant enhancement in the formation of isonicotinic acid was observed compared with that of isonicotinamide. These results suggest that the pathway of a carbonyl-centered radical might be favored upon coordination to the Fe(II) owing to the π-back-bonding effect promoted by this metal center; therefore, the isoniazid metal complex could serve as a potential metallodrug. Enzymatic inhibition assays conducted with InhA showed that the cyanoferrate moiety is not the major player involved in this inhibition but the presence of isoniazid is required in this process. Other isoniazid metal complexes, [Ru(CN)(5)(izd)](3-) and [Ru(NH(3))(5)(izd)](2+) (where izd is isoniazid), were also unable to inhibit InhA, supporting our proposed self-activating mechanism of action. We propose that isoniazid reactivity can be rationally modulated by metal coordination chemistry, leading to the development of novel anti-TB metallodrugs.

This study describes a simple and efficient procedure to synthesize a novel series of fourteen 4-substituted N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyrimidin-2-amines, where the 4-substituents are H, CH3, C6H5, 4-FC6H4, 4-CH3C6H4, 4-CH3OC6H4 and 2-Furyl; from the cyclocondensation reaction of N-[5-(pyridinyl)-1H-1,2,4-triazol-3-yl]guanidines with 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones. The reactions were carried out in ethanol under reflux for 18 h and led to 40–68% yields. N-(Pyridyl-triazolyl)guanidine precursors were further obtained from reactions of cyanoguanidine with nicotinic or isonicotinic acid hydrazides and the halogenated enones from trifluoroacetylation of enolethers or acetals.

The crystalline nanocluster phase, in which nanoscale metal oxide clusters are self-assembled in three-dimensional periodic arrays, is described. The crystalline assembly of nanoparticles functionalized with technologically relevant ligands offers the opportunity to obtain unambiguous structural information that can be combined with theoretical calculations based on the known geometry and used to interpret spectroscopic and other information. A series of Ti/O clusters up to approximately 2.0 nm in diameter have been synthesized and functionalized with the adsorbents catechol and isonicotinic acid. Whereas the isonicotinate is always adsorbed in a bridging monodentate mode, four different adsorption modes of catechol have been identified. The particles show a significantly larger variation of the Ti-O distances than observed in the known TiO(2) phases and exhibit both sevenfold overcoordination and five- and fourfold undercoordination of the Ti atoms. Theoretical calculations show only a moderate dependence of the catecholate net charge on the geometry of adsorption. All of the catechol-functionalized clusters have a deep-red color due to penetration of the highest occupied catechol levels into the band gap of the Ti/O particles. Spectroscopic measurements of the band gap of the Ti(17) cluster are in good agreement with the theoretical values and show a blue shift of approximately 0.22 eV relative to those reported for anatase nanoparticles.

Introduction: Isonicotinic acid hydrazide (INH) was coupled to diethylenetriaminepentaacetic acid (DTPA) via amide linkage. Primary object of the present invention was to propose a novel INH derivative based on DTPA, which form stable complexes with most of lanthanides and transition metals in periodic table. Another object of the present invention was to introduce a chelating group in INH without compromising its biological activity for early diagnosis of infection using nuclear medicine and MR techniques. Methods: The DTPA-bis(INH) was synthesized in high yield using simple synthetic procedure. Radiochemical purity was ascertained chromatographically using different solvent system. Blood kinetics in rabbits and biodistribution in mice were studied. The ability of DTPA-bis(INH) to target infection site in vivo was assessed by gamma scintigraphic studies of normal rabbit and rabbit with induced tuberculosis. Preliminary clinical studies were done in patients with known tuberculoses lesions. Results: DTPA-bis(INH) was characterized using spectroscopic techniques. The complex was successfully labeled with 99m Tc radionuclide with more than 95% labeling efficiency. It was found stable up to 24h. Blood kinetics showed rapid first pass clearance with biological half life t1/2 (F) of 11 min. Biodistribution in tuberculose induced Balb/c mice showed target to muscle ratio 4.53 ± 0.89 after 4h post injection. Gamma scintigraphy of normal as well as rabbits with induced tuberculosis was carried out. An appreciable activity was visualized in liver and kidneys. In infection induced rabbit similar pattern was observed with the accumulation of activity at the tuberculose site at 4 h post injection. Clinical scintigraphy with 99m Tc-DTPA-bis(INH) clearly indicated the accumulation of the tracer at the tuberculose region in six patients (median age 46 years, range 28-69 years, females; n=2 and males; n=4) which were found positive for Mycobacterium tuberculosis in bacterial culture analysis. Conclusions: From the present work it can be concluded that the radiolabeled DTPA-bis(INH) accumulates at the site of infection.

Fifteen antivitamins were tested, at various concentrations, on the adult olive fruit fly, Dacus oleae. Fly survival was affected by the following antivitamins, indicating in parenthesis the antagonized vitamin: benzimidazole (B-12), a-picolinic acid (nicotinic acid), deoxypyridoxine (pyridoxine), neopyrithiamine (thiamine), and a-tokopherol quinone (vit. E). Egg production was significantly reduced by the same antivitamins, plus, dl-desthiobiotin (biotin), aminopterin (folic acid), isonicotinic acid, nicotinic acid diethylamide (nicotinic acid), and dehydroascorbic acid (vit. C). Fertility was significantly affected by: benzimidazole (B-12), dl-desthiobiotin (biotin), aminopterin (folic acid), isonicotinic acid (nicotinic acid), deoxypyridoxine (pyridoxine), neopyrithiamine (thiamine), a-tokopherol quinone (vit. E), and dehydroascorbic acid (vit. C). Zusammenfassung Zur Wirkung von Antivitaminen auf die Uberlebenszeit und Reproduktion der Olivenfruchtfliege, Dacus oleae Gmel. (Dipt., Tephritidae) Es wurde die Wirkung von 15 Antivitaminen in verschiedenen Konzentrationen auf adulte Olivenfruchtfliegen, D. oleae, untersucht. Folgende Substanzen beeinflusten die Uberlebenszeit (unter Angabe des antagonistischen Vitamins): Benzimidazol (B-12), a-Picolinic-Saure (Nikotinsaure), Deoxypyridoxin (Pyridoxin), Neopyrithiamin (Thiamin) und a-Tokopherol Chinon (Vit. E). Die Eizahl wurde signifikant durch die gleichen Antivitamine und die im folgenden genannten reduziert: dl-Desthiobiotin (Biotin), Aminopterin (Folsaure), Isonikotinsaure, Nikotinsaure-Diethyamid (Nikotinsaure) und Dehydroascorbinsaure (Vitamin C). Die Fertilitat wurde signifikant beeinflust durch: Benzimidazol (B-12), dl-Desthiobiotin (Biotin), Aminpterin (Folsaure), Isonikotinsaure (Nikotinsaure), Deoxypyridoxin (Pyridoxin, Neopyrithiamin), a-Tokopherol Chinon (Vit. E) und Dehydroascorbinsaure (Vit. C).

A fullerene-isoniazid conjugate has been synthesized by 1, 3 dipolar cycloaddition reaction of fullerene (C(60)) with isonicotinic acid (4-formyl-benzylidene) hydrazide and N-methylglycine. The identity and purity of the compound was confirmed by elemental analysis, (1)H NMR, (13)C NMR and MALDI-TOF mass spectral analysis. Stable water suspension, in which the particles of the synthesized conjugate were made to aggregate in nanosize, was successfully tested for antimycobacterial activity against Mycobacterium avium and strains of Mycobacterium tuberculosis- H(37)Rv & H6/99 at concentration as low as 0.50 microg/mL.

A homology model of the p110alpha catalytic subunit of PI3Kalpha was generated from the p110gamma crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kalpha and gamma binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs.

Nicotinic acid and nicotinamide belong to the water-soluble vitamins, and they have many physiological and pharmacological functions in various organisms. In this study, we investigated the differentiation-inducing ability of nicotinic acid-related compounds in chronic myelogenous leukemia K562 cell line. Proliferation of K562 leukemia cells was inhibited by several nicotinic acid-related compounds. Hemoglobin content was increased by nicotinic acid and by isonicotinic acid. Isonicotinic acid increased gamma-globin mRNA expression as much as sodium butyrate did. The nuclei of nicotinic acid and of isonicotinic acid-treated cells decreased in size and the chromatin became more condensed. It was verified that nicotinic acid and isonicotinic acid induced erythroid differentiation in K562 cells. Expression of glycophorin A was increased by sodium butyrate. In contrast, it was decreased by nicotinic acid and by isonicotinic acid, suggesting that these compounds differentiate K562 to erythrocytes through different pathways than sodium butyrate does. Our data perhaps provide useful information as to the mechanisms of cell differentiation.