Design, synthesis, and biological evaluation of isatin-indole-3-carboxaldehyde hybrids as a new class of xanthine oxidase inhibitors.

A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.

Rational approaches for the design of various GABA modulators and their clinical progression.

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.

pH and thermo-responsive tetronic micelles for the synthesis of gold nanoparticles: effect of physiochemical aspects of tetronics.

Micelles of the star shaped block polymers "tetronics" were employed for the synthesis of gold (Au) nanoparticles (NPs) under the effect of pH and temperature variation. The presence of the diamine core in the tetronic macromolecule made its micelles highly pH responsive, thereby dramatically altering the physiochemical properties. Likewise, a high degree of hydration made the micelles temperature sensitive. UV-visible studies, transmission electron microscopy (TEM), gel electrophoresis, and structure optimization by energy minimization were applied to understand the physiochemical aspects of tetronic micelles and their further role in the synthesis of Au NPs. Synthesis of Au NPs was triggered by the surface cavities of the micelles and hence the NPs simultaneously adsorbed on the micelle surface. Low pH induced high hydration and temperature responsive well defined vesicular morphologies bearing Au NPs, while high pH produced mainly large and compact compound micelles carrying NPs. Both pH and temperature responsive behaviors of different tetronics significantly influenced the synthesis of Au NPs and thus demonstrated their ability to act as nanoreactors for the materials synthesis under different experimental conditions.

Protein mixtures of environmentally friendly zein to understand protein-protein interactions through biomaterials synthesis, hemolysis, and their antimicrobial activities.

Industrially important zein protein has been employed to understand its interactions with two model proteins bovine serum albumin (BSA) and cytochrome c (Cyc,c) following the in vitro synthesis of Au NPs so as to expand its applicability for biological applications. Interactions were studied under the effect of temperature variation by UV-visible and fluorescence emission studies. Temperature induced unfolding in the protein mixtures indicated their degree of mutual interactions through simultaneous nucleation of gold nanoparticles (Au NPs) and their subsequent shape control effects. Zein + BSA mixtures showed favorable protein-protein interactions over the entire mole fraction range with maximum close to x(BSA) = 0.24, whereas zein + Cyc,c showed such interactions only in the zein rich region with significant demixing in the Cyc,c rich region of the mixtures. Both hydrophobic as well as hydrophilic domains in the unfolded states were driving such interactions in the case of zein + BSA mixtures while demixing was the result of the predominant hydrophilic nature of Cyc,c and its self-aggregation behavior in the Cyc,c rich region in contrast to the predominant hydrophobic nature of zein. Zein + BSA mixtures produced small roughly spherical Au NPs fully coated with protein, whereas the demixing zone of zein + Cyc,c mixtures generated highly anisotropic NPs with little protein coating. To explore their biological applications, protein conjugated NPs of both mixtures were subjected to hemolysis where NPs coated with the former mixture showed little hemolysis and may act as drug delivery vehicles in systemic circulation in comparison to the latter. Both kinds of NPs further demonstrated their extraordinary antimicrobial activities with different kinds of strains and proved to be highly important environmentally friendly biomaterials.

Trends in childhood immunisation amongst Muslim children of Punjab (India): An empirical study.

India's immunisation programme is one of the largest in the world and achieved great success over the years, however, some significant gaps are still observable in terms of achieving universal immunisation of children. Religion has emerged as a strong correlate for immunisation rates at national, state and global level. It has been observed that the rate of immunisation among children from Muslim families is comparatively less at global as well as at national level. Therefore, the paper attempts to understand immunisation trends among Muslims children from the north-western Indian state of Punjab. Based on the cross-sectional study of 400 households from district Sangrur of Punjab, results of the study show that rate of full immunisation among children from Muslim families was 88 per cent and none of the children were non-immunised. Reasons stated for partial immunisation of children included distrust of the government and belief that it would cause infertility amongst children. The present study reveals that religion per se does not appear to be influence rates of full immunisation. Geographical location, embeddedness of the community in the larger political and social milieu of their area, reach and acceptance of health workers at grassroots level emerge as strong factors contributing to higher rates of immunisation amongst Muslim children of Malerkotla.

A Comparative Evaluation of the Effects of Three Remineralizing Agents on Bleached Enamel: A Scanning Electron Microscopy (SEM) Analysis.

With the emerging concern of patients on esthetics, bleaching has become quite popular to get that "Shining White Smile." However, bleaching chemicals used on enamel's surface have been a clinical issue due to the fact that they might cause a variety of side effects, including sensitivity, gingival irritation, dentinal sensitivity, demineralization, and changes in the enamel's surface morphology. As a result, it is important to investigate different remineralizing agents that help to reduce the adverse effects. The researchers in this in-vitro study used a scanning electron microscope (quanta 200 SEM, California, USA) and a universal testing machine to assess the effects of three remineralizing products such as Tooth Mousse Plus (GC Corporation, India), Tooth Min (Abbott, India), and Elsenz (Group Pharmaceuticals Ltd, India) on bleached enamel. Based on the data available, we determined that bleaching greatly reduces the enamel microhardness of permanent human premolars; however, this loss could be recovered with a remineralizing agent. Tooth Mousse Plus is the most effective remineralizing agent among the three, followed by Elsenz and, finally, Tooth Min.

Synthetic heterocyclic derivatives as promising xanthine oxidase inhibitors: An overview.

Inhibition of xanthine oxidase (XO) is an effective and most prominent therapeutic approach for the management of gout. Discovery of its association in the pathophysiology of diabetes, cardiovascular disorders, etc., widened its therapeutic horizons. Limited drug candidates in clinical practice along with side effects forced researchers to develop more efficacious and safer XO inhibitors for the management of gout and other disorders associated with XO hyperactivity. In this regard, this review focus on (a) various drug candidates in clinical practice and under clinical trials, (b) Development of various heterocyclic motifs as XO inhibitors in last two decades and (c) various patented synthetic XO inhibitors.

Biomineralization of gold nanoparticles by lysozyme and cytochrome C and their applications in protein film formation.

Lysozyme (Lys) and cytochrome c (Cyc,c) proteins were used as mild reducing and stabilizing agents to synthesize gold nanoparticles (NPs) at precisely 40 and 80 degrees C. All reactions were monitored simultaneously by UV-visible measurements to determine changes in the nature of the protein during the course of reaction. The synthesis of Au NPs caused the simultaneous denaturation of protein due to the formation of bioconjugate NPs, and the denaturation temperature decreased with the number of NPs. Lys entrapped NPs in a typical gel state, and Cyc,c carried them on well-defined micelles at 80 degrees C or in the form of long fibrils or strands at 40 degrees C. The shape, size, and arrangement of bioconjugate NPs were characterized by atomic force microscopy and transmission electron microscopy measurements. Purified bioconjugate NPs were further used in zein protein film formation. The resulting films were characterized by photophysical and mechanical measurements. The induction of bioconjugate NPs made protein films isotropic and relatively more brittle (with a greater effect for Cyc,c than for Lys conjugate NPs) than in their absence and was considered to be well suited for biomedical applications.

How PEO-PPO-PEO triblock polymer micelles control the synthesis of gold nanoparticles: temperature and hydrophobic effects.

Aqueous micellar solutions of F68 (PEO(78)-PPO(30)-PEO(78)) and P103 (PEO(17)-PPO(60)-PEO(17)) triblock polymers were used to synthesize gold (Au) nanoparticles (NPs) at different temperatures. All reactions were monitored with respect to reaction time and temperature by using UV-visible studies to understand the growth kinetics of NPs and the influence of different micellar states on the synthesis of NPs. The shape, size, and locations of NPs in the micellar assemblies were determined with the help of TEM, SEM, and EDS analyses. The results explained that all reactions were carried out with the PEO-PPO-PEO micellar surface cavities present at the micelle-solution interface and were precisely controlled by the micellar assemblies. Marked differences were detected when predominantly hydrophilic F68 and hydrophobic P103 micelles were employed to conduct the reactions. The UV-visible results demonstrated that the reduction of gold ions into nucleating centers was channeled through the ligand-metal charge-transfer complex (LMCT) and carried out by the surface cavities. Excessive hydration of the surface cavities in the case of F68 micelles produced a few small NPs, but their yield and size increased as the micelles were dehydrated under the effect of increasing temperature. The results concluded that the presence of well-defined predominantly hydrophobic micelles with a compact micelle-solution interfacial arrangement of surface cavities ultimately controlled the reaction.

Antibacterial and phytochemical screening of Anethum graveolens, Foeniculum vulgare and Trachyspermum ammi.

BACKGROUND: Anethum graveolens Linn., Foeniculum vulgare Mill. and Trachyspermum ammi L. are widely used traditional medicinal plants to treat various ailments. To provide a scientific basis to traditional uses of these plants, their aqueous and organic seed extracts, as well as isolated phytoconstituents were evaluated for their antibacterial potential. METHODS: Antibacterial activity of aqueous and organic seed extracts was assessed using agar diffusion assay, minimum inhibitory concentration and viable cell count studies; and their antibacterial effect was compared with some standard antibiotics. The presence of major phytoconstituents was detected qualitatively and quantitatively. The isolated phytoconstituents were subjected to disc diffusion assay to ascertain their antibacterial effect. RESULTS: Hot water and acetone seed extracts showed considerably good antibacterial activity against all the bacteria except Klebsiella pneumoniae and one strain of Pseudomonas aeruginosa. Minimum inhibitory concentration for aqueous and acetone seed extracts ranged from 20-80 mg/ml and 5-15 mg/ml respectively. Viable cell count studies revealed the bactericidal nature of the seed extracts. Statistical analysis proved the better/equal efficacy of some of these seed extracts as compared to standard antibiotics. Phytochemical analysis showed the presence of 2.80 - 4.23% alkaloids, 8.58 - 15.06% flavonoids, 19.71 - 27.77% tannins, 0.55-0.70% saponins and cardiac glycosides. CONCLUSION: Antibacterial efficacy shown by these plants provides a scientific basis and thus, validates their traditional uses as homemade remedies. Isolation and purification of different phytochemicals may further yield significant antibacterial agents.

Design, Synthesis, Antimicrobial Evaluation, and Molecular Modeling Studies of Novel Indolinedione-Coumarin Molecular Hybrids.

Keeping in view various pharmacological attributes of indole and coumarin derivatives, a new series of indolindione-coumarin molecular hybrids was rationally designed and synthesized. All synthesized hybrid molecules were evaluated for their antimicrobial potential against Gram-negative bacterial strains (Escherichia coli and Salmonella enterica), Gram-positive bacterial strains (Staphylococcus aureus and Mycobacterium smegmatis), and four fungal strains (Candida albicans, Alternaria mali, Penicillium sp., and Fusarium oxysporum) by using the agar gel diffusion method. Among all synthetics, compounds K-1 and K-2 were found to be the best antimicrobial agents with the minimum inhibitory concentration values of 30 and 312 µg/mL, against Penicillium sp. and S. aureus, respectively. The biological data revealed some interesting facts about the structure-activity relationship which state that the electronic environment on the indolinedione moiety and carbon chain length between indolinedione and triazole moieties considerably affect the antimicrobial potential of the synthesized hybrids. Various types of binding interactions of K-2 within the active site of S. aureus dihydrofolate reductase were also streamlined by molecular modeling studies, which revealed the possible mechanism for potent antibacterial activity of the compound.

Monocarbonyl Curcumin-Based Molecular Hybrids as Potent Antibacterial Agents.

Keeping in view various pharmacological attributes of curcumin, coumarin, and isatin derivatives, triazole-tethered monocarbonyl curcumin-coumarin and curcumin-isatin molecular hybrids have been synthesized and evaluated for their antibacterial potential against Gram-positive (Enterococcus faecalis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) human pathogenic bacterial strains. Among all hybrid molecules, A-4 and B-38 showed the most potent antibacterial activity with inhibition zones of 29 and 31 mm along with MIC values of 12.50 and 6.25 µg/mL, respectively. Structure-activity relationship that emerged from biological data revealed that the two-carbon alkyl chain between triazole and coumarin/isatin moiety is well tolerable for the activity. Bromo substitution at the fifth position of isatin, para-cholo substitution in the case of curcumin-isatin, and para-methoxy in the case of curcumin-coumarin hybrids on ring A of curcumin are most suitable groups for the antibacterial activity. Various types of binding interactions of A-4 and B-38 within the active site of dihydrofolate reductase (DHFR) of S. aureus are also streamlined by molecular modeling studies, suggesting their capability in completely blocking DHFR.

Amoebic Colonic Perforation Presenting as Peritonitis in Emergency, Incidence and Outcome: Our Experience.

OBJECTIVES: Amoebiasisis a common parasitic infection and fulminant amoebic colitis remains a very rare complication of this disease. The objective of the present study was to find the incidence and outcome of perforation peritonitis due to amoebic colitis in MMIMSR, Mullana, Ambala, India. MATERIAL AND METHODS: 200 patients with perforation peritonitis were studied retrospectively, out of which 22 cases had colonic perforation, were selected over a period of five years, between 2012 to 2017, at MMIMSR Mullana. All patients had undergone emergency laparotomy and cases with amoebic colonic perforation established on histopathology were studied in terms of incidence, clinical presentation and outcomes. RESULTS: Out of 200 emergency exploratory laparotomies carried out during 2012-2017 at MMIMSR, Mullana, 22 (11%) patients had amoebic colonic perforation. The disease was more common among men as compared to women (21:1). The mean age of patients was 60±10 years. Symptom duration ranged from 1 to 8 days. 15 (68%) patients had historyof chronic alcohol intake and 2 (9%) had a recent episode of loose stools. Chest X-ray showed free gas under the diaphragm in 45% (10/22) of patients. Ultrasonography whole abdomen showing associated liver abscess was seen in 8/22 (36%) patients. Intraoperatively caecal perforation was seen in 20 cases, out of which 16 had concomitant ascending colon perforation and 2 sigmoid colon perforation. Bowel resection was performed depending upon the site and extent of the colon involved- right hemicolectomy (16), limited ileocolic resection (4) and sigmoidectomy (2). Proximal diversion stoma was made in all cases. Postoperative complications encountered were wound infection in 20 (91%) cases, followed by burst abdomen in 8 (36%) cases, stoma related complication in 6 (27%) cases. The overall mortality rate due to sepsis was 54% (12/22). CONCLUSION: Although amoebiasis is a common parasitic infection, fulminant amoebic colitis remains a very rare complication with a reported incidence of 1%. Even with aggressive management of this entity, patients have got a poor prognosis. Resection with exteriorization of bowel is the current gold standard treatment in such cases.

Lamellar phase supported synthesis of colloidal gold nanoparticles, nanoclusters, and nanowires.

Gold nanoparticles (Au NP) have been synthesized in aqueous phase under ambient conditions in the presence of a series of various cationic double chain as well as dimeric (gemini) surfactants. The spacer chain and twin tail length of these surfactants has been systematically varied to see the effect of hydrophobicity on their capping ability. It has been observed that the increase in the length of spacer chain (from 12-2-12 to 12-6-12) and twin tails (from 10-2-10 to 14-2-14) significantly increases the lamellar phase formation and which in return acts as a wonderful template to accommodate the NP in the form of nanoclusters and nanowires. The lamellar phase practically facilitates the nucleation of Au degrees and produces large NP (15 +/- 2 nm). All reactions have also been carried out in the presence of beta-cyclodextrin (CYC) which has strong ability to complex with surfactant tail. The presence of CYC induces a tendency to form nanowire and it is more prominent in the case of surfactants with longer spacer group.

Effect of sodium dodecylsulfate and dodecyltrimethyl ammonium bromide on the morphologies of gold nanoparticles in the presence of poly(amidoamine) dendrimers.

The synthesis of gold nanoparticles has been carried out in aqueous phase in the presence of both ionic surfactants (i.e., sodium dodecylsulfate (SDS) and dodecyltrimethylammonium bromide (DTAB)) and poly(amidoamine) dendrimers (PAMAM). It has been observed that the fluoroderivative of 2G PAMAM (2D) acts as reducing agent in reducing Au(lll) to Au(0) leading to the formation of fine gold nanoparticles. This process has been further evaluated in the presence of fixed amounts of both SDS and DTAB in their respective pre and post micellar concentration regions. The presence of SDS leads to the appearance of clear ordered morphologies such as triangular, hexagonal, spherical, and rod shaped, while the presence of DTAB does not show this effect. The formation of nanoparticles in triangular morphologies is more significant in the premicellar concentration range of SDS whereas hexagonal morphologies in the post micellar concentration range. On the contrary, increase in the DTAB concentration from pre to post micellar range only reduces the size of gold nanoparticles without the appearance of any ordered morphology. The formation of ordered gold nanoparticles in the presence of SDS has been further attributed to the significant SDS-dendrimer interactions and an appropriate mechanism has been proposed to justify the results.

Synthesis of colloidal gold nanoparticles of different morphologies in the presence of triblock polymer micelles.

The Au nanoparticles have been synthesized in the presence of micellar solutions of fixed concentration (i.e. 1.4 x 10(-3) mol dm(-3)) of each poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), triblock polymers (TBP), such as P103, P84, P123, and F127. The nanoparticles have also been synthesized in the presence of mixed micellar solutions of binary TBP mixtures such as P103+ P84 and P103+P123. In the previous case, "raspberry type" Au nanoparticle-TBP aggregates have been observed in which nanoparticles of 2-3 nm have been uniformly distributed throughout the TBP micelle. On the other hand, in the latter case, apart from such aggregates, prominent ordered morphologies of nanoparticles such as rod, sphere, triangle, and hexagonal have also been observed with much larger dimensions. This has been attributed to the nucleation process occurring in the mixed micelles rather than in the micelles of single TBP components.

Nanoparticle Surface Specific Adsorption of Zein and Its Self-assembled Behavior of Nanocubes Formation in Relation to On-Off SERS: Understanding Morphology Control of Protein Aggregates.

Zein, an industrially important protein, is characterized in terms of its food and pharmaceutical coating applications by using surface enhanced Raman spectroscopy (SERS) on Au, Ag, and PbS nanoparticles (NPs). Its specific surface adsorption behavior on Ag NPs produced self-assembled zein nanocubes which demonstrated on and off SERS activity. Both SERS characterization as well as nanocube formation of zein helped us to understand the complex protein aggregation behavior in shape controlled morphologies, a process with significant ramifications in protein crystallization to achieve ordered morphologies. Interestingly, nanocube formation was promoted in the presence of Ag rather than Au or PbS NPs under in situ synthesis and discussed in terms of specific adsorption. Zein fingerprinting was much more clear and enhanced on Au surface in comparison to Ag while PbS did not demonstrate SERS due to its semiconducting nature.

Mixed micelles of monomeric and dimeric cationic surfactants with phospholipids: effect of hydrophobic interactions.

Surface tension (gamma) and time resolved fluorescence quenching (TRFQ) measurements have been performed on the binary mixtures of monomeric as well as dimeric alkylammonium bromides with l-alpha-dimyristoylphosphatidycholine (DMPC) and L-alpha-dipalmitoylphosphatidycholine (DPPC). The critical micelle concentration (cmc) has been evaluated from the gamma measurements. The gamma plots show two breaks in the gamma versus [total surfactant] curves in most of the cases. The first break (C1) has been attributed to the mixed vesicle formation process. The break down of the vesicles leads to the mixed micellization between the surfactant and phospholipid monomers at the second break (C2). The amount of surfactant used in the vesicle breakdown process (DeltaC) increases linearly with the increase in the amount of phospholipid and depends significantly on the hydrophobicities of the cationic components. The surface area per molecule (a) evaluated from the gamma plots indicates compact monolayer formation in the case of monomeric surfactants with lower hydrophobicities and reverse is observed for dimeric surfactants. The pyrene life time (tau) of the solubilized pyrene in the hydrophobic environment of mixed micelles, fully supports the conclusion that derived from a.

Antagonistic mixing behavior of cationic gemini surfactants and triblock polymers in mixed micelles.

Conductance (kappa), pyrene fluorescence (I1/I3), cloud point (C(P)), and Krafft temperature (K(T)) measurements have been carried out for various dimethylene bis(alkyldimethylammonium bromide) (gemini) surfactants with different poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock polymers (TBP). From the kappa and I1/I3 studies, the critical micelle concentrations of mixed micelle formation between the gemini and TBP have been determined using regular solution theory. It has been observed that mixed micelle formation in all the binary mixtures of gemini+TBP occurs due to the unfavorable mixing, the magnitude of which decreases with increased hydrophobicity of the gemini component. The results are further supported by evaluating the mean micelle aggregation number and enthalpy of fusion from fluorescence and Krafft temperature measurements, respectively.

Mixed micelles of benzyldimethyltetradecylammonium chloride with tetradecyltrimethylammonium and tetradecyltriphenylphosphonium bromides: a head group contribution.

Mixed micelle formation by tetradecyltrimethylammonium (TTAB) and tetradecyltriphenylphosphonium bromides (TTPB) with benzyldimethyltetradecylammonium chloride (BTDACl) was studied with the help of conductivity and Kraft point measurements. The BTDACl + TTAB mixtures showed synergistic interactions whereas those of BTDACl + TTPB indicated weak antagonistic behavior. From Kraft temperature measurements, the enthalpy of fusion (H(1)(0)) from solid hydrated BTDACl to the liquid state in the presence of TTAB or TTPB was computed. It was found that DeltaH(1)(0) was much more positive for BTDACl + TTPB than for BTDACl + TTAB mixtures.