Synthesis of novel nicotinamide susbstituted phthalocyanine and photodynamic antomicrobial chemotherapy evaluation potentiated by potassium iodide against the gram positive S. aureus and gram negative E. coli.

In the present work, we propose the synthesis of novel nicotinamide subsituted phthlocyanine photosensitizer (PS) and characterized by FTIR, UV-visible, H-NMR and MALDI Toff spectroscopy. Nicotinamide plays a vital rule in the central nervous system and its potential as a therapeutic for neurodegenerative disease. Nicotinamide substituted PS (3) efficiently produced ROS via type-1 process as measured by DCF assay. We observed that our PS after red light illumination (22 J/cm2) killed gram positive S. aureus upto 3 log reduction. Furher the addition of Potassium Iodide (100 mM) significantly potentiated PS at lower concentrations and enhanced the bacterial killing upto 6 log reduction against the S. aureus. We further found that the synergistic effect of PS and KI also eradicated the gram negative E. coli strain at lower concentraion of PS and found to killed E. coli upto 5 log reduction under the red light illumination at 22 J/cm2 of light dose. The conjugation of such biologically important form of vitamin B3 with PS would be a great addition and could pav the way for the novel photodynamic agent in the treatement of cancer and infectious diseases. A new symmetrical Nicotinamide tetrasubstituted zinc phthalocyanine (3) was synthesized. Upon addition of potassium Iodide with PS, the PS exhibited significant photodynamic activity with 5-6 logs reduction in bacterial load was achieved.

Effectiveness of a pharmacist-led structured group-based intervention in improving medication adherence and glycaemic control among type 2 diabetes mellitus patients: A randomized controlled trial.

BACKGROUND: A pharmacist-led structured group-based intervention (MEDIHEALTH) was formulated to improve medication adherence among Malay type 2 diabetes mellitus (T2DM) patients in the Malaysian state of Sarawak. OBJECTIVES: The objective of this study was to examine the effectiveness of MEDIHEALTH and its mechanism of impact for improving medication adherence and the glycated haemoglobin (HbA1c) level. METHODS: A two group and parallel randomised controlled trial with a twelve months follow-up period was conducted at two primary health clinics in Malaysia that were surrounded by Malay communities. Malay T2DM patients whose HbA1c was >7% and total score on the Self-Efficacy for Appropriate Medication Use Scale (SEAMS) was <26 were recruited and parallelly randomised to the MEDIHEALTH or usual care (control) groups. The extended theory of planned behaviour was employed to test the mechanism of impact. Repeated measure analysis of variance was used to assess the difference in the estimated marginal mean of the SEAMS scores and HbA1c level between the intervention and control groups at different times. RESULTS: A total of 142 participants were recruited and randomised; three from the intervention group and eight from the control group withdrew before receiving any treatment. Hence, 68 participants in the intervention group and 63 in the control group were included for analyses. The MEDIHEALTH group had a significantly greater increase in the SEAMS score compared to the control group (p < 0.001) at one, three, six and twelve months post-intervention. There was also a significantly greater reduction in HbA1c in the MEDIHEALTH compared to the control group at one, three, six and twelve months post-intervention (p < 0.001). These improvements were mediated by enhancements in perceived behavioural control and knowledge about medications. CONCLUSIONS: The MEDIHEALTH may improve medication adherence and glycaemic control among Malay T2DM patients.

1,4-Fluoroamination of 1,3-Enynes en Route to Fluorinated Allenes.

The regioselective synthesis of fluorinated allenes via a metal-free 1,4-fluoroamination of 1,3-enynes is presented. This method employs commercially available N-fluorobenzenesulfonimide serving as both the nitrogen source and the fluorine source, affording access to various tetrasubstituted allenes in a straightforward and atom-economic pathway. Preliminary mechanistic studies and theoretical studies revealed that this reaction might undergo an intimate ion-pair mechanism.

Synthesis of difluoromethylated allenes through trifunctionalization of 1,3-enynes.

Organofluorine compounds have shown their great value in many aspects. Moreover, allenes are also a class of important compounds. Fluorinated or fluoroalkylated allenes might provide an option as candidates for drug and material developments, as allenes allow a great number of valuable transformations. Herein, we report a metal-free synthesis of difluoromethylated allenes via regioselective trifunctionalization of 1,3-enynes. This method proceeds through double C-F bond formation with concomitant introduction of an amino group to the allene. Synthetic applications are conducted and preliminary mechanistic studies suggest that a two-step pathway is involved. DFT calculations revealed an unusual dibenzenesulfonimide-assisted fluorination/fluoroamination with NFSI. In addition, kinetic reaction study revealed the induction period of both major and side products to support the proposed reaction mechanism. This work offers a convenient approach for the synthesis of a range of difluoromethylated allenes and is also a rare example of trifunctionalization of 1,3-enynes.

Copper(I)-catalyzed tandem reaction: synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl diacyl peroxides, azidotrimethylsilane, and alkynes.

A copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction for the synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl diacyl peroxides, azidotrimethylsilane, and terminal alkynes is reported. The alkyl carboxylic acids is for the first time being used as the alkyl azide precursors in the form of alkyl diacyl peroxides. This method avoids the necessity to handle organic azides, as they are generated in situ, making this protocol operationally simple. The Cu(I) catalyst not only participates in the alkyl diacyl peroxides decomposition to afford alkyl azides but also catalyzes the subsequent CuAAC reaction to produce the 1,2,3-triazoles.

2'-Aryl and 4'-arylidene substituted pyrazolones: As potential α-amylase inhibitors.

Acarbose and voglibose are well-known α-amylase inhibitors used for the management of type-II diabetes mellitus. Unfortunately, these well-known and clinically used inhibitors are also associated with several adverse effects. Therefore, there is still need to develop the safer therapy. Despite of a broad spectrum of biological significances of pyrazolone, it is infrequently evaluated for α-amylase inhibition. Current study deals with the synthesis and biological screening of aryl and arylidene substituted pyrazolones 1-18 for their potential α-amylase inhibitory activity. Structures of synthetic derivatives 1-18 were identified by different spectroscopic techniques. All compounds 1-18 (IC50 = 1.61 ±â€¯0.16 µM to 2.38 ±â€¯0.09 µM) exhibited significant to moderate inhibitory potential when compared to standard acarbose (IC50 = 1.46 ±â€¯0.26 µM). A number of derivatives including 8-12 (IC50 = 1.68 ±â€¯0.1 µM to 1.97 ±â€¯0.07 µM) and 14-16 (IC50 = 1.61 ±â€¯0.16 µM to 1.93 ±â€¯0.07 µM) were found to be significantly active. Limited SAR suggested that different substitutions on compounds do not have any significant effect on the inhibitory potential. Compounds were found to be mixed-type inhibitors revealed by kinetic studies. However, in silico study was identified a number of key features participating in the interaction with the binding site of α-amylase enzyme.

DNA physical interaction mediated b-lymphoma treatment offered by tetra benzimidazole-substituted zinc (ii) phthalocyanine derivative.

Role of heterocyclic compounds with nitrogen substitution in therapeutic frontiers is well established. The efforts made in this study are directed to dissect the biological significance of benzimidazole-substituted zinc phthalocyanine derivative. Its capacity to act as an anticancer agent against the 2 B-lymphoma cell lines (low-grade and high-grade malignancy) was found out by recording florescence using Alamar blue dye. Further cytotoxic effect at the DNA level was analyzed by performing agarose gel electrophoresis. Molecular docking studies made mechanistic details crystal clear by showing potential dual binding modes employed for interaction with DNA that include minor groove binding and intercalation between bases. This advocates this derivative as potential anticancer agent and deserves further rounds of mechanistic study for its final journey to serve as a marketed drug.

New Bis-Pyrazolones as Potential Leads for ROS Inhibition; Environment Friendly Green Synthesis, Structural Characterization, and In Vitro Studies.

BACKGROUND: Pyrazolones have identified as significant antioxidant agents and many marketed and clinically prescribed NSAIDs have pyrazolone ring as main scaffold. METHOD: Keeping in consideration the antioxidant potential of pyrazolone scaffold, new bispyrazolones 3-30 were synthesized by a green and enviroment friendly reaction route, in which two equivalents of 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-ol were treated with one equivalent of benzaldehyde derivatives without any catalyst. All compounds were structurally characterzied by 1H-NMR and FAB analysis. 13C-NMR of selected compounds was also recorded. All compounds gave satisfactory elemental analyses and found in good agreement with calculated values. RESULTS: Synthetic bis-pyrazolones 3-30 were evaluated for their oxidative burst inhibitory effect of zymosan stimulated whole blood phagocytes by using luminol enhanced chemilluminescence technique. All molecules demonstrated the potent ROS inhibition activity in the range of IC50 = 1.2 ± 0.1-48.8 ± 3.9 µM as compared to the standard ibuprofen (IC50 = 54.2 ± 9.2 µM). The purity of active compounds was checked by HPLC. CONCLUSION: This study has identified a number of non-acidic lead molecules for future research on ROS inhibitors.

Synthesis of Thiocarbohydrazones and Evaluation of their in vitro Antileishmanial Activity.

BACKGROUND: Leishmaniasis is a protozoan parasitic vector-borne disease which is endemic in 88 tropical countries. Infected sandfly is the main vector of this disease, while there are several other vectors, parasites, and reservoirs involved in the transmission of this disease. Leishmania donovani, L. infantum, and L. chagasi are common disease causing species, transmitted through sandflies. Leishmaniasis is a neglected tropical disease with broad spectrum of clinical manifestations. Cutaneous leishmaniasis is prevalent in many countries, including Pakistan. METHODS: Thiocarbohydrazones (1-20) were synthesized through one pot method by refluxing thiocarbahydrazide with different substituted benzaldehydes in ethanol in the presence of acetic acid as a catalyst. These synthetic compounds were evaluated for their potential antileishmanial activity in vitro against Leishmania major promastigotes. RESULTS: Compounds 5-8, 11, 14, 16, 17, 19 and 20 were reported earlier, while compounds 2-4, 9, 10, 12, 13 and 15 were identified as were derivatives. Compounds 1-20 demonstrated antileishmanial activities with IC50 values between 1.63 ± 0.05 - 64.82 ± 0.17 µM, as compared to the standard drug pentamidine (IC50 = 5.09 ± 0.04 µM). Compounds 2 (IC50 = 1.63 ± 0.05 µM), 11 (IC50 = 2.33 ± 0.01 µM), 4 (IC50 = 11.03 ± 0.20 µM), and 10 (IC50 = 11.63 ± 0.06 µM) displayed comparable antileishmanial activities to the standard drug pentamidine. However, compounds 13, 15-17, and 20 with IC50 values 36.95 ± 0.025, 64.82 ± 0.17, 64.27 ± 0.38, 62.34 ± 0.38, and 40.47 ± 0.05 µM, respectively, showed a moderate antileishmanial activity. In contrast, compounds 1, 3, 5-9, 12, 14, 18, and 19 demonstrated less than 50% growth inhibition of promestigotes of L. major, and thus considered as inactive. CONCLUSION: In thiocarbohydrazone derivatives, different substituents at aryl part may be responsible for a varying degree of antileishmanial activity in vitro. Consequently, these compounds might have a potential for further studies as a new class of antileishmanial agents.

Unprecedented chemosensing behavior of novel tetra-substituted benzimidazole zinc(II) phthalocynine for selective detection of Bi3+ ion: Synthesis, characterization and ROS generation.

In this work, synthesis of novel symmetrical 4-(2-bromo-4-(5-bromo-1H-benzo[d] imidazol-2-yl) phenoxy) tetra substituted zinc phthalocyanine has been reported. The novel benzimidazole zinc phthlocynine compound (3) has been characterized by MALDI-TOF MS, FT-IR, UV-vis, and 1H NMR spectroscopy. This new compound 3 displayed excellent selectivity towards Bi3+ ion in the presence of other competitive ions including Ca2+, Cd2+, Co2+ Cu2+, Fe3+, Hg2+, Sn2+, Mg2+, Na+, Ni2+ and Pb2+ respectively. Upon addition of Bi3+ into the solution of compound 3 in DMSO, dramatic change was observed in the Q- and the B-bands in UV-visible spectra as a result of donor acceptor interactions. Reactive oxygen species (ROS) were also studied using 2,7-dichlorofluorescin diacetate (DCFH-DA) a fluorescent probe which is converted to highly fluorescent dichlorofluorescein (DCF) in the presence of ROS. This property of non-aggregating zinc phthalocyanine is promising as a photosensitizer in photodynamic therapy of cancer.

Syntheses of 4,6-dihydroxypyrimidine diones, their urease inhibition, in vitro, in silico, and kinetic studies.

A library of 4,6-dihydroxypyrimidine diones (1-35) were synthesized and evaluated for their urease inhibitory activity. Structure-activity relationships, and mechanism of inhibition were also studied. All compounds were found to be active with IC50 values between 22.6±1.14-117.4±0.73µM, in comparison to standard, thiourea (IC50=21.2±1.3µM). Kinetics studies on the most active compounds 2-7, 16, 17, 28, and 33 were performed to investigate their modes of inhibition, and dissociation constants Ki. Compounds 2, 3, 7, 16, 28, and 33 were found to be mixed-type of inhibitors with Ki values in the range of 7.91±0.024-13.03±0.013µM, whereas, compounds 4-6, and 17 were found to be non-competitive inhibitors with Ki values in the range of 9.28±0.019-13.05±0.023µM. In silico study was also performed, and a good correlation was observed between experimental and docking studies. This study is continuation of our previously reported urease inhibitory activity of pyrimidine diones, representing potential leads for further research as possible treatment of diseases caused by ureolytic bacteria.

Dihydropyrano [2,3-c] pyrazole: Novel in vitro inhibitors of yeast α-glucosidase.

Inhibition of α-glucosidase enzyme activity is a reliable approach towards controlling post-prandial hyperglycemia associated risk factors. During the current study, a series of dihydropyrano[2,3-c] pyrazoles (1-35) were synthesized and evaluated for their α-glucosidase inhibitory activity. Compounds 1, 4, 22, 30, and 33 were found to be the potent inhibitors of the yeast α-glucosidase enzyme. Mechanistic studies on most potent compounds reveled that 1, 4, and 30 were non-competitive inhibitors (Ki=9.75±0.07, 46±0.0001, and 69.16±0.01µM, respectively), compound 22 is a competitive inhibitor (Ki=190±0.016µM), while 33 was an uncompetitive inhibitor (Ki=45±0.0014µM) of the enzyme. Finally, the cytotoxicity of potent compounds (i.e. compounds 1, 4, 22, 30, and 33) was also evaluated against mouse fibroblast 3T3 cell line assay, and no toxicity was observed. This study identifies non-cytotoxic novel inhibitors of α-glucosidase enzyme for further investigation as anti-diabetic agents.

Crystal structure of 2-[2-(benz-yloxy)benzyl-idene]malono-nitrile.

In the title benzyl-idenemalono-nitrile derivative, C17H12N2O, the dihedral angles between the central benzene ring and the Y-shaped C=C(CN)2 group (r.m.s. deviation = 0.006 Å) and the terminal benzene ring are 12.72 (8) and 37.60 (11)°, respectively. The Car-O-Csp (3)-Car torsion angle is -174.52 (13)° and the major twist between the aromatic rings occurs about the Csp (3)-Car bond. Weak aromatic π-π stacking [centroid-centroid separation = 3.7784 (13) Å; slippage = 1.21 Å] between inversion-related pairs of the central benzene rings is observed in the crystal.

Crystal structure of 6-amino-4-(3-bromo-4-meth-oxy-phen-yl)-3-methyl-2,4-di-hydro-pyrano[2,3-c]pyrazole-5-carbo-nitrile dimethyl sulfoxide monosolvate.

In the pyrazole mol-ecule of the title solvate, C15H13BrN4O2·C2H6OS, the dihedral angle between the benzene ring and the mean plane of the di-hydro-pyrano[2,3-c]pyrazole ring system [r.m.s deviation = 0.031 (2) Å] is 86.71 (14)°. In the crystal, the pyrazole mol-ecules are linked by N-H⋯N hydrogen bonds, forming a layer parallel to (10-1). The pyrazole and dimethyl sulfoxide mol-ecules are connected by an N-H⋯O hydrogen bond.