Synthesis of Novel N-Acylhydrazones and Their C-N/N-N Bond Conformational Characterization by NMR Spectroscopy.

In this article, a synthesis of N'-(benzylidene)-2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazides and their structural interpretation by NMR experiments is described in an attempt to explain the duplication of some peaks in their 1H- and 13C-NMR spectra. Twenty new 6-methyl-1H-pyrazolo[3,4-b]quinoline substituted N-acylhydrazones 6(a-t) were synthesized from 2-chloro-6-methylquinoline-3-carbaldehyde (1) in four steps. 2-Chloro-6-methylquinoline-3-carbaldehyde (1) afforded 6-methyl-1H-pyrazolo[3,4-b]quinoline (2), which upon N-alkylation yielded 2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetate (3). The hydrazinolysis of 3 followed by the condensation of resulting 2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazide (4) with aromatic aldehydes gave N-acylhydrazones 6(a-t). Structures of the synthesized compounds were established by readily available techniques such as FT-IR, NMR and mass spectral studies. The stereochemical behavior of 6(a-t) was studied in dimethyl sulfoxide-d6 solvent by means of 1H NMR and 13C NMR techniques at room temperature. NMR spectra revealed the presence of N'-(benzylidene)-2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazides as a mixture of two conformers, i.e., E(C=N)(N-N) synperiplanar and E(C=N)(N-N)antiperiplanar at room temperature in DMSO-d6. The ratio of both conformers was also calculated and E(C=N) (N-N) syn-periplanar conformer was established to be in higher percentage in equilibrium with the E(C=N) (N-N)anti-periplanar form.

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer's heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 µM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 µM, respectively. Various informative structure-activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.

Modulative effect of a new hydrazide derivative on wheat-induced pulmonary inflammation in rats.

NEW FINDINGS: What is the central question of this study? What is the mechanism of wheat-induced pulmonary inflammation and how does a hydrazide derivative modulate it? What is the main finding and its importance? A hydrazide derivative significantly reduced wheat-induced pulmonary inflammation in a rat model mainly by down-regulating inflammatory cell infiltration, pathological lesions in the lungs and the level of pro-inflammatory cytokines, COX-1, COX-2 and T-cell proliferation. ABSTRACT: We investigated the ameliorative anti-inflammatory effect of a previously synthesized hydrazide derivative (N'-(4-methoxybenzylidene)-6-(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazide; MD) as an immunomodulator in a newly developed allergen-induced pulmonary inflammation (AIPI) rat model. Wheat and thresher dust were used as allergens to induce pulmonary inflammation while MD was used to reverse the inflammatory response. Blood and bronchoalveolar lavage fluid (BALF) were collected after killing the rats and inflammatory cells were counted. Histological analysis of lung airways was carried out by haematoxylin and eosin and periodic acid-Schiff staining while the level of total serum IgE, interleukin (IL)-4, IL-5 and cyclooxygenase (COX)-1 in BALF and in vitro T-cell proliferation in spleen were measured through enzyme-linked immunosorbent assay. mRNA expression level of IL-4, IL-5, IL-13, transforming growth factor ß (TGF-ß), interferon-γ, tumour necrosis factor α, COX-1 and COX-2 was evaluated by qRT-PCR. A liver and kidney function test was used to observe any toxic impact of MD. The results indicated that 2 mg of wheat and thresher dust led to higher levels of inflammatory cytokines in the blood, BALF and lung airways of rats. MD potentially down-regulated the inflammatory cell infiltration in BALF and pathological lesions in the lung airways of AIPI rats. MD significantly suppressed the elevated total serum IgE, along with IL-4, IL-5, IL-13, TGF-ß, COX-1 and COX-2 mRNA expression and T-cell proliferation in spleen. In conclusion, MD at 10 mg kg-1 exhibited a significant reduction in all the markers in both wheat- and thresher dust-induced pulmonary inflammation mainly by inhibiting pro-inflammatory cytokine production and T-cell proliferation. The data suggest that inhibition of the T-cell response may be responsible for the modulative effect of MD in an AIPI rat model.

6-Chloro-N-(2-meth-oxy-phen-yl)pyridazin-3-amine.

The asymmetric unit of the title compound, C(11)H(10)ClN(3)O, contains two geometrically different mol-ecules, A and B, in both of which the pyridazine rings are essentially planar with r.m.s. deviations of 0.0137 and 0.0056Å, respectively. In mol-ecule A, the dihedral angle between the pyridazine and benzene rings is 6.5 (2)°, whereas in mol-ecule B it is 27.93 (7)°. In mol-ecule B, an intramolecular N-H⋯O hydrogen bond forms an S(5) ring motif. In both molecules, S(6) ring motifs are present due to non-classical C-H⋯N hydrogen bonds. The π-π inter-actions between the pyridazine rings of A mol-ecules [3.4740 (13) Å] and B mol-ecules [3.4786 (17) Å] have very similar centroid-centroid separations. π-π Inter-actions also occur between the benzene rings of B mol-ecules with a centroid-centroid separation of 3.676 (2) Šand a slippage of 1.02 Å. In the crystal, the mol-ecules are linked into chains extending along [010] by C-H⋯N and C-H⋯Cl interactions.

Investigation and Discrimination of Ballpoint Pen Inks by Analytical Techniques and Chemometrics.

A population study has been performed for Pakistani ballpoint pen inks of blue, black, red, and green colors (a total of four colors) commercially used in Pakistan. Ballpoint pen inks have been investigated and discriminated by using UV/Vis spectroscopy and FTIR spectroscopy. We have calculated and compared the results in terms of discriminating power (DP). The statistical techniques of principal component analysis and cluster analysis have been applied on obtained data. By visual comparison, the best DP is obtained for green ballpoint pen inks, i.e., 0.866 by using UV/Vis spectroscopy and FTIR techniques. Black and red ballpoint pen inks showed the highest DPs by using UV/Vis spectroscopy; however, blue ballpoint pen inks got the highest DP by using FTIR spectroscopy. DP has been improved by using chemometric techniques and higher DPs are obtained as compared to visual examination.

Discrimination of Pakistani Fountain Pen Inks by Gas Chromatography-Mass Spectrometry (GC-MS).

In developing countries, the chances of fraud in written documents are comparatively high. Therefore, comparison of fountain pen inks is especially imperative in examination of forensic questioned documents. We have investigated the use of the gas chromatography-mass spectrometry technique in profiling and discrimination of fountain pen ink used in Pakistan for forensic purpose. The main purpose of this study was to discriminate different Pakistani fountain pen inks. The datum for Pakistani inks of fountain pen is not obtainable. In this research study, blue, black, and green colors fountain pen inks commercially used in Pakistan have been extracted from paper using micropunch and then investigated using the gas chromatography-mass spectrometry technique. Gas chromatography-mass spectrometry (GC-MS) was used to differentiate various brands of different colors of fountain pen inks based on their chemical composition. Molecular ion peaks for different components were obtained, and components were identified on the basis of detected ions. Results have been calculated and compared in terms of discriminating power (D.P.). The D.P. for blue, black, and green inks of fountain pen was 1.0 by using the gas chromatography-mass spectrometry technique.

3-Chloro-6-[2-(cyclo-pentyl-idene)hydrazin-1-yl]pyridazine.

The asymmetric unit of the title compound, C(9)H(11)ClN(4), contains two virtually planar mol-ecules that differ in conformation about the bond connecting the hydrazine and pyridazine units. The 3-chloro-6-hydrazinylpyridazine and cyclo-pentane groups are oriented at dihedral angles of 4.5 (3) and 8.8 (4)° in the two mol-ecules. In the crystal, the mol-ecules form a one dimensional polymeric structure extending along the a axis via N-H⋯N hydrogen bonds. The crystal stucired was an inversion twin [ratio of the twin domains = 0.73 (9):0.27 (9)].

N-Phenyl-6-(1H-pyrazol-1-yl)pyridazin-3-amine.

The mol-ecule of title compound, C(13)H(11)N(5), is essentially planar (r.m.s. deviation = 0.0440 Å) and an intra-molecular C-H⋯N hydrogen bond generates an S(6) motif. In the crystal, mol-ecules are connected into chains by inter-molecular N-H⋯N and C-H⋯N hydrogen bonds. In addition, π-π stacking inter-actions are observed between the pyrazole and pyridazine rings [inter-planar distance = 3.6859 (10) Å].

3-[(2E)-2-(Butan-2-yl-idene)hydrazin-yl]-6-chloro-pyridazine.

The asymmetric unit of the title compound, C(8)H(11)ClN(4), contains two independent mol-ecules (A and B) with slightly different conformations: the dihedral angles between the 3-chloro-6-hydrazinylpyridazine units and butyl side chains are 4.5 (2) and 11.98 (16)°. In the crystal, the A and B mol-ecules are linked by a pair of N-H⋯N hydogen bonds, generating an R(2) (2)(8) loop.

3-Chloro-6-[(E)-2-(1-phenyl-ethyl-idene)hydrazin-yl]pyridazine.

Two independent mol-ecules are present in the asymmetric unit of the title compound, C(12)H(11)ClN(4), (Z' = 2): the dihedral angles between the phenyl and pyridizine rings are 8.35 (10) and 37.64 (6)°. In the crystal, the two mol-ecules form inversion dimers with R(2) (2)(8) ring motifs through inter-molecular N-H⋯N hydrogen bonds. The crystal structure is stabilized by π-π inter-actions between the pyridazine rings of symmetry-related molecules. In one of the independent mol-ecules, the centroid-centroid separations are 3.6927 (13) and 3.7961 (13) Å, whereas in the other, the separations are 3.6909 (13) and 3.9059 (13) Å.

3-Chloro-6-[2-(propan-2-yl-idene)hydrazin-yl]pyridazine.

In the title compound, C(7)H(9)ClN(4), the 3-chloro-6-hydrazinylpyridazine unit is planar (r.m.s. deviation = 0.0219 Å) and is oriented at a dihedral angle 4.66 (27)° with respect to the propan-2-yl-idene group. In the crystal, the mol-ecules are linked into non-planar dimers due to a crystallographic twofold rotation via N-H⋯N hydrogen bonds with R(2) (2)(8) graph-set ring motifs.

3-Chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine.

In the title compound, C(9)H(9)ClN(4), the dihedral angle between the aromatic rings is 6.25 (9)°. The whole mol-ecule is approximately planar (r.m.s. deviation = 0.070 Å). In the crystal, π-π inter-actions between the centroids of the pyridazine rings [separation = 3.5904 (10) Å] occur.

N-(4-Methyl-phen-yl)-6-(pyrazol-1-yl)pyridazin-3-amine.

In the title compound, C(14)H(13)N(5), the pyrazole ring is disordered over two orientations in a 0.571 (10):0.429 (10) ratio and the dihedral angle between the pyridazine ring and the benzene ring is 28.07 (10)°. In the crystal, pairs of N-H⋯N and C-H⋯N hydrogen bonds link the mol-ecules into dimers, with the aid of a crystallographic twofold axis. The packing is consolidated by further C-H⋯N bonds and weak C-H⋯π inter-actions.

3-Chloro-6-(1H-pyrazol-1-yl)pyridazine.

The title compound, C(7)H(5)ClN(4), is almost planar (r.m.s. deviation = 0.022 Å). The dihedral angle between the aromatic rings is 2.82 (5)°. The packing results in polymeric chains extending along the a axis. In the crystal, mol-ecules are connected to each other through inter-molecular C-H⋯N hydrogen bonds, resulting in R(2) (2)(10) ring motifs.

Ethyl 5-amino-1-(6-chloro-pyridazin-3-yl)-1H-pyrazole-4-carboxyl-ate.

In the title compound, C(10)H(10)ClN(5)O(2), the dihedral angle between the aromatic rings is 0.16 (9)°. Two S(6) ring motifs are formed due to intra-molecular N-H⋯N and N-H⋯O hydrogen bonds. In the crystal, inversion dimers linked by pairs of N-H⋯N hydrogen bonds generate R(2) (2)(14) [or R(4) (4)(10) via the intra-molecular hydrogen bonds] ring motifs. Polymeric chains propagating in [210] are formed as a result of inter-linking the dimers by pairs of C-H⋯N inter-actions, completing R(2) (2)(6) ring motifs.

N-(2-Methyl-phen-yl)-6-(1H-pyrazol-1-yl)pyridazin-3-amine.

The title compound, C(14)H(13)N(5), crystallizes with two crystallographically independent mol-ecules in the unit cell. The two mol-ecules form dimers through inter-molecular N-H⋯N and C-H⋯N hydrogen bonds. The hydrogen-bonding motifs are R(2) (2)(8) for both the N-H⋯N and C-H⋯N inter-actions. The pyrazole and pyrimidine rings form dihedral angles of 6.2 (3) and 8.3 (3)° with each other and the dihedral angles between the pyrazole and benzene rings are 54.9 (2) and 58.6 (2)°. The benzene rings of neighbouring dimers also exhibit C-H⋯π inter-actions.

Stability-indicating HPLC-PDA assay for simultaneous determination of paracetamol, thiamine and pyridoxal phosphate in tablet formulations.

With the increased number of multi-drug formulations, there is a need to develop new methods for simultaneous determinations of drugs. A precise, accurate and reliable liquid chromatographic method was developed for simultaneous determination of paracetamol, thiamine, and pyridoxal phosphate in pharmaceutical formulations. Separation of analytes was carried out with an Agilent Poroshell C18 column. A mixture of ammonium phosphate buffer (pH = 3.0), acetonitrile and methanol in the ratio of 86:7:7 (V/V/V) was used as the mobile phase pumped at a flow rate of 1.8 mL min-1. Detection of all three components, impurities and degradation products was performed at the selected wavelength of 270 nm. The developed method was validated in terms of linearity, specificity, precision, accuracy, LOD and LOQ as per ICH guidelines. Linearity of the developed method was found in the range 17.5-30 µg mL-1 for thiamine, 35-60 µg mL-1 for pyridoxal phosphate and 87.5-150 µg mL-1 for paracetamol. The coefficient of determination was ≥ 0.9981 for all three analytes. The proposed HPLC method was found to be simple and reliable for the routine simultaneous analysis of paracetamol, thiamine and pyridoxal phosphate in tablet formulations. Complete separation of analytes in the presence of degradation products indicated selectivity of the method.

A miniaturized electronic sensor for instant monitoring of ethanol in gasohol fuel blends.

Gasoline-ethanol (gasohol) fuel blends have gained considerable attention in the petroleum and energy sectors as relatively cheaper and greener high-octane alternative fuels with gasoline-comparable efficiency in modern transportation vehicles. However, due to different combustion rates the relative concentration of ethanol in gasohol fuel blends may vary over time. Furthermore, there is a need to monitor ethanol concentration in fuel blends for quality control applications. This article reports a miniaturized electronic sensor based on an interdigital capacitor (IDC) as the transducer and a dual-imprinted titania-polyaniline composite film as the receptor. The device has an active surface area of 0.9 cm2 and is easy to fabricate. The receptor material is synthesized by imprinting ethanol in both titania sol (EITS, the matrix) and polyaniline nanoparticles (EIPani, the filler), and subsequently mixing them to obtain a dual-imprinted EITS-EIPani composite. The structural and morphological characteristics of the receptor layers are determined with Fourier transform infrared (FTIR) spectroscopy and atomic force microscopy (AFM), respectively. The IDC devices are fabricated with pristine EITS and dual-imprinted EITS-EIPani composite to test their metrological sensor characteristics in standard ethanol solutions and real-time gasohol fuel blends. The instant shift in capacitance is measured upon exposure to different concentrations of ethanol. These devices show excellent sensitivity and selectivity patterns and demonstrate reliable sensor response toward ethanol in different gasohol fuel blends with 1-10 vol% ethanol. The results of this study reveal that these miniaturized ethanol sensors are potentially useful for rapid analysis of ethanol in gasohol and may be optimized for onboard fuel quality control applications.

Pyrazolobenzothiazine-based carbothioamides as new structural leads for the inhibition of monoamine oxidases: design, synthesis, in vitro bioevaluation and molecular docking studies.

Two new series of pyrazolobenzothiazine-based carbothioamides (3a-o and 4a-o) were synthesized using saccharin as the starting material. The synthesized derivatives were investigated for their ability to inhibit monoamine oxidases (MAO). Compound 3b was found to be a very potent MAO-A inhibitor with an IC50 value of 0.003 ± 0.0007 µM, while compound 4d was the most effective inhibitor of MAO-B having an IC50 value of 0.02 ± 0.001 µM. Molecular docking studies were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. The synthetic and computational investigations in the current work suggested that these newly identified inhibitors may serve as a powerful starting point for the exploration and optimization of potential therapeutic agents targeting Parkinson's disease.

Breast Cancer in Pakistan a Critical Appraisal of the Situation Regarding Female Health and Where the Nation Stands?

Breast cancer (BC) is the most common malignancy of women worldwide. In the past it was considered as disease of older middle aged women, but the incidence of BC in young females is growing in recent years concordant with studies in Pakistan. In this paper, we reviewed the mutant functions of tumor suppressor genes (BRCA1, BRCA2, p53, ATM and PTEN), epigenetic transformation and involvement of estrogen receptors in development of breast cancer. We further reviewed the current situation of BC in Pakistan that depicts a higher incidence in young females. According to SKMCH and RC data, age group 4549 years is more prone to BC with high rate of incidence 45.42%. A few studies explored the high expression of ER, PR and HER2/neu in Pakistani females. Moreover, presence of BRCA1 (c.1961dupA) mutation in Pakistani shows concordance with data in different areas of world. But we are unable to find an authentic study that can explore epigenetic based transformation of breast tumors in Pakistan. This area of research needs more attention to explore the complete picture of BC in Pakistan.