Multistep Synthesis of Analogues of Remdesivir: Incorporating Heterocycles at the C-1' Position.

Studies suggest that the 1'ß-CN moiety in remdesivir sterically clashes with the Ser861 residue of the RNA-dependent-RNA polymerase (RdRp), causing a delayed chain termination in the RNA replication process. Replacing C1'ß-CN with 5-membered heterocycles such as tetrazoles, oxadiazoles, and triazoles can augment the inhibitory activity and pharmacokinetic profile of C-nucleotides. Synthesis of tetrazole-, triazole-, and oxadiazole-integrated C1' analogues of remdesivir was attempted using general synthetic routes. The final compounds 26, 28, and 29 did not inhibit viral replication; however, the synthetic intermediates, i.e., 27 and 50, exhibited an IC90 = 14.1 µM each. The trifluoromethyl-substituted 1,2,4-oxadiazole 59 showed an IC90 of 33.5 µM. This work adds to the growing evidence of the beneficial medicinal impact of C1,1'-disubstituted C-nucleotides.

Self-care practices and quality of life of filariasis patients in a gram panchayat of Paschim Burdwan district, West Bengal, India.

Background & objectives: Self-care management is one of the important components in the goal of elimination of lymphatic filariasis (LF) and Quality of Life (QoL) has become an important deliverable in the present day health care system. The objective was to assess the self-care management of the affected limb and to find out the quality of life who were suffering from lymphoedema. Methods: This was a community-based cross-sectional epidemiological study conducted during 2019-2020 in a Gourbazar gram panchayat area of Paschim Burdwan district of West Bengal, India. QoL was assessed by Lymphatic Filariasis Specific Quality of life Questionnaire (LFSQQ). Results: Total 115 LF patients were identified with a mean age of 53.9 years. About 26.1% correctly knew the management of the affected area. Out of the 33 patients having cracked skin, around 39.4% used to take care of the affected skin. Overall, median quality of life score was found to be 77.84 (65.90-89.20). Age-wise, median score gradually decreased with increase in age except in the age group of 50-60 years. Males had higher score compared to females (79.54 vs. 76.13). Activity domain score was found to be lowest followed by mobility score, while social and psychological domain score was found to be good. Interpretation & conclusion: Self-care practice is not known to the affected patients. Time has also come to integrate measures like rehabilitation, psychological intervention, social assistance in addition to self-care management to put up a holistic approach of the existing program.

Drain in laparoscopic cholecystectomy in acute calculous cholecystitis: a randomised controlled study.

BACKGROUND: There is paucity of evidence regarding the role of drain in laparoscopic cholecystectomy (LC) in acute calculous cholecystitis (ACC), and surgeons have placed the drains based on their experiences, not on evidence-based guidelines. This study aims to assess the value of drain in LC for ACC in a randomised controlled prospective study. PATIENTS AND METHODS: All patients with mild and moderate ACC undergoing LC were assessed. Preoperatively, patients with choledocholithiasis, Mirizzi syndrome and biliary stent were excluded. Intraoperatively or postoperatively, patients with complications, partial cholecystectomies and malignancies were excluded. Patients were randomised using computer-generated random numbers into two groups at the end of cholecystectomy before closure. Requirement of radiologically guided (ultrasonography () or CT) percutaneous aspiration/drainage of symptomatic intra-abdominal collection or reoperation; continuation of parenteral antibiotics beyond 24 hours or change in antibiotics empirically or based on peritoneal fluid culture sensitivity; requirement of postoperative USG or CT scan based on postoperative clinical course; wound infection rates; postoperative pain using numeric rating scale at 6 and 24 hours; and the duration of hospital stay in both groups were noted. RESULTS: Forty-two out of 50 consecutive patients were randomised into two equal groups. Pain score at 6 and 24 hours was less in patients without drain. All other complication rates and duration of stay were similar in both groups. CONCLUSIONS: Drains should not be placed routinely after LC in ACC as it increases pain and does not help in detecting or decreasing complications.

Stabilization of Dispersed Oil Droplets in Nanoemulsions by Synergistic Effects of the Gemini Surfactant, PHPA Polymer, and Silica Nanoparticle.

Nanoemulsion systems comprising n-heptane (oleic component), stabilized by the {gemini surfactant (14-6-14 GS) + polymer [partially hydrolyzed poly-acrylamide (PHPA)] + silica (SiO2) nanoparticle} shell and dispersed in aqueous phase, were synthesized by ultrasonication (high-energy method). Influence of ultrasonication time on nanoemulsion kinetics was investigated to predict the saturation droplet diameter. Morphological analysis by transmission electron cryomicroscopy imaging showed that oleic phase appears as uniformly dispersed spherical droplets in 14-6-14 GS-stabilized nanoemulsion, which on PHPA addition changes into a network structure consisting of larger oil droplets. 14-6-14 + PHPA + SiO2 nanoemulsion systems show more effective packing arrangement with irregular-shaped (nonspherical) droplets. Dynamic light scattering studies identified droplet size distribution profiles in the range 4.2-25.4 nm for the surfactant-stabilized nanoemulsion, 125.9-358.8 nm for the surfactant-polymer nanoemulsion, and 88.4-222.3 nm for the surfactant-polymer-nanoparticle-based nanoemulsion in optimal dosage(s). Statistical analyses were performed using normal, log-normal, and Cauchy-Lorentz distribution functions. A modified form of Hinze theory was employed to model droplet behavior in analyzed nanoemulsion systems. Zeta potential values of nanoemulsions were studied at different time intervals to determine kinetic stability as well as corroborate Hinze model findings. In summary, this article aims at investigating nanoemulsion droplet stability by thorough examination of electrostatic repulsive barrier and steric hindrance effects.

Experimental Investigation of the Synergistic Effect of Two Nonionic Surfactants on Interfacial Properties and Their Application in Enhanced Oil Recovery.

In chemically enhanced oil recovery (EOR), surfactants are conventionally used to lower the interfacial tension (IFT) at the water-oil interface, alter the rock wettability, and help in the emulsification of trapped oil after primary and secondary modes of recovery. A mixture of surfactants is usually more effective than a single surfactant with enhanced surface or interfacial properties. The primary objective of this study is to examine the synergistic effects of two nonionic surfactants (Tergitol 15-S-12 and PEG 600) on surface properties, such as surface tension, IFT, and wettability alteration, in the context of EOR. The optimum composition of the surfactant mixture was obtained by surface tension measurement, and it has been found that the Tergitol 15-S-12 and PEG 600 mixture shows better synergistic effect with a minimum surface tension value of 30.3 mN/m at 225 ppm concentration of Tergitol 15-S-12 and 1 wt % of PEG 600. The surfactant mixture with optimum composition shows an ultra-low IFT of 0.672 mN/m at optimum salinity. The wettability alteration study was conducted in a goniometer by observing the change of the contact angle of an oil-wet sandstone rock in the presence of the formulated chemical slugs at different concentrations, and the results show a shift in the wettability of rock from the oil-wet to the water-wet region. The wettability alteration behavior of oil-wet rock is established using X-ray diffraction analysis of sandstone rock and zeta potential measurements of the chemical slugs. The efficacy of the optimized chemical slug for EOR was checked by a core flooding experiment, and an additional recovery of 17.73% of the original oil in place was observed.

Application of α-MnO2 nanoparticles for residual oil mobilization through surfactant polymer flooding.

Injection of surfactant and polymer slug is among the most effective chemical enhanced oil recovery processes. The only problem encountered with the surfactant polymer (SP) flooding is the loss of surface-active agents that reduce the efficiency of surfactants in the chemical slug. Various attempts to modify SP flooding have been made previously so that the surfactant loss due to adsorption could be reduced. Nanoparticles (NPs) are one of the most effective ways of reducing surfactant adsorption as surfactant particles are held in the liquid phase by nanoparticles, resulting in lower surfactant losses due to adsorption. However, the high cost of the NPs limits their use on the field scale. To encounter this problem, the present study focuses on the application of the manganese dioxide NPs, synthesized through a green route that is economically viable. These NPs are found to be cost-effective as compared to commercially available NPs as well as the synthesis of these NPs does not require the use of toxic chemicals. The 1000 ppm NPs effectively reduced the surfactant adsorption by 46%. The surface tension was lowered from 29.4 to 26.1 mN/m when 1000 ppm NPs were applied to 2500 ppm surfactant solution. Also, the nanoparticles were found to increase the viscosity of the chemical slug by increasing the solid particles present in the slug. The sand pack flooding experiments were carried out to assess the crude oil mobilization ability of the NPs assisted SP flooding. The oil recovery was found to increase from 5% of the original oil in place, resulting in ~ 75% of the crude oil recovery, which was only ~ 70% when NPs were not introduced into the system.

Protective therapy with novel chromone derivative against Leishmania donovani infection induces Th1 response in vivo.

BACKGROUND: Visceral leishmaniasis is a chronic protozoan disease caused by Leishmania donovani, an obligatory intracellular parasite that resides and multiplies within macrophages of the reticuloendothelial system. The aim of this study was to evaluate the efficacy of nine novel synthetic chromone derivatives as antileishmanial molecules in experimental murine visceral leishmaniasis. METHODS: In vitro activity of the molecules (2, 5 and 10 µg/ml) was assessed against promastigotes of both pentavalent antimonial-responsive strain AG83 and pentavalent antimonial-resistant strain GE1F8R at days 2 (48 h), 4 (96 h) and 6 (144 h). The efficacy of the most efficient chromone derivative [C-(6-Methyl-4-oxo-4H-1-benzopyran-3-yl)-N-(p-tolyl) nitrone], designated here as NP1, was also tested against intracellular amastigotes in vitro and in vivo. RESULTS: NP1, 5 µg/ml, inhibited the growth of AG83 and GE1F8R promastigotes by 98.57% (day 4) and 75.75% (day 6), respectively, and also inhibited the growth of intracellular amastigotes by 85% (day 3), compared to DMSO control. Treatment of L. donovani-infected mice with NP1 resulted in a 70% significant decrease in parasite load in the spleen in the 7th week after infection (5 mice in each group), with associated induction of interferon-γ synthesis by dose 2 (37.5 mg/kg body weight) compared to DMSO control. Dose 2 was found efficient over dose 1 (25 mg/kg body weight). CONCLUSIONS: The novel synthetic chromone derivative is effective in the treatment of visceral leishmaniasis and induces the synthesis of interferon-γ in rodent models.

Application of Novel Colloidal Silica Nanoparticles in the Reduction of Adsorption of Surfactant and Improvement of Oil Recovery Using Surfactant Polymer Flooding.

Surfactant polymer flooding is one of the most common chemical enhanced oil recovery techniques, which improves not only the microscopic displacement of the fluid through the formation of the emulsion but also the volumetric sweep efficiency of the fluid by altering the viscosity of the displacing fluid. However, one constraint of surfactant flooding is the loss of the surfactant by adsorption onto the reservoir rock surface. Hence, in this study, an attempt has been made to reduce the adsorption of the surfactant on the rock surface using novel colloidal silica nanoparticles (CSNs). CSNs were used as an additive to improve the performance of the conventional surfactant polymer flooding. The reduction in adsorption was observed in both the presence and absence of a polymer. The presence of a polymer also reduced the adsorption of the surfactant. Addition of 25 vol % CSNs effectively reduced the adsorption of up to 61% in the absence of a polymer, which increased to 64% upon the introduction of 1000 ppm polymer in the solution at 2500 ppm of the surfactant concentration at 25 °C. The adsorption of surfactant was also monitored with time, and it was found to be increasing with respect to time. The adsorption of surfactant increased from 1.292 mg/g after 0.5 days to 4.179 mg/g after 4 days at 2500 ppm of surfactant concentration at 25 °C. The viscosity, surface tension, and wettability studies were also conducted on the chemical slug used for flooding. The addition of CSNs effectively reduced the surface tension as well as shifted the wettability toward water-wet at 25 °C. Sand pack flooding experiments were performed at 60 °C to access the potential of CSNs in oil recovery, and it was found that the addition of 25 vol % CSNs in the conventional surfactant polymer chemical slug aided in the additional oil recovery up to 5% as compared to that of the conventional surfactant polymer slug.

A mechanistic investigation of low salinity water flooding coupled with ion tuning for enhanced oil recovery.

Oil recovery by low salinity water flooding (LSWF) from carbonate reservoirs has gained tremendous attention in recent years due to its cost-effectiveness and environment-friendly nature. The mechanisms of low salinity water flooding for enhanced oil recovery are very complex and depend on the mineralogy of the formation rock, properties of injection brine and reservoir fluids. The present work aimed at the optimization of salinity and concentration of potential determining ions (PDIs) in injection water for enhanced oil recovery from carbonate reservoirs. Initially, we conducted a series of experiments on the dilution effect of seawater (SW) with the help of rock/fluid and fluid/fluid interactions via interfacial tension (IFT), zeta potential and contact angle measurements. This offered an optimum salinity (20dSW) with an 11% increase in recovery of the original oil in place (OOIP) over the SW injection in secondary flooding mode. Then, the ion tuning was done on the optimum salinity (20dSW) by manipulating the PDIs (Ca2+, SO4 2- and Mg2+) while keeping ionic strength constant. The properties of ion tuned brine were optimized by zeta potential and contact angle measurements. The core flooding experiments performed with the injection of designed ion tuned water obtained by dilution and ion tuning of SW showed more than 20% OOIP as incremental recovery over the SW injection. Effluent analysis after the flooding confirms that the main mechanisms for enhanced oil recovery include calcite dissolution and wettability alteration due to interplay of PDIs.

Characterization of Hydrophobically Modified Polyacrylamide in Mixed Polymer-Gemini Surfactant Systems for Enhanced Oil Recovery Application.

The study deals with the synthesis and characterization of the hydrophobically modified polyacrylamide (HMPA) copolymer and its functional property evaluation in mixed polymer-gemini surfactant systems for application in enhanced oil recovery (EOR). The copolymer was initially prepared in the laboratory using acrylamide and N-phenylacrylamide monomer units via an addition polymerization route. The synthesized copolymer was characterized by Fourier transform infrared and proton nuclear magnetic resonance to identify suitable functional groups in the compound. Gel permeation chromatography tests showed that the polymer has a molecular weight of 2.098 × 105 Da. Copolymer solution showed favorable tolerance to variations in temperature and salinity. Salt precipitation studies identified tolerance limit up to 25% NaCl at a temperature of 343 K. Viscosity of HMPA fluids showed an increase with increasing concentration. Interestingly, salt addition until 1.0% NaCl showed an increase in solution viscosity owing to the electrostatic shielding of the HMPA polymer and strengthened intermolecular association of the hydrophobic groups. This behavior is against physicochemical properties observed in the case of conventional polymers but exhibits promising functionality in EOR processes wherein better oil mobility control is desired under subsurface conditions. Gemini surfactants accommodate onto "vacant adsorption" sites onto the liquid surface, improving the interfacial adsorption property and reducing surface tension. In the presence of gemini surfactant polymers forming mixed nanoemulsion fluid systems with favorable pseudoplastic character, their viscosities initially increase with surfactant concentration due to binding of surfactant molecules to hydrophobic junctions of polymer chains to form mixed micelles. Eventually, polymer hydrophobes get saturated with surfactant micelles, and viscosity decreases due to electrostatic repulsion among surfactant micelles. Dynamic light scattering analyses confirmed the formation of nanoemulsion droplets with sizes of <310 nm in the case of {surfactant + copolymer} encapsulation. Zeta potential measurements showed that an increase in 14-6-14 gemini surfactant concentration enhanced the stability of nanoemulsion fluid due to increasing zeta potential values. However, the nonionic SF-6-SF surfactant does not affect the zeta potential of nanoemulsions. Surfactant addition reduced the oil-aqueous interfacial tension of polymer solutions to several magnitudes of an order of 10-1 to 10-2 mN/m. Contact angle studies identified the ability of the polymer as well as polymer-surfactant nanoemulsions to alter the wettability of the reservoir rock from the intermediate-wet (90°-120°) to strongly water-wet state (<20°) at different temperatures. Analyzed formulations showed favorable miscibility with crude oil at 343 K. In summary, HMPA/gemini surfactant-based emulsions possess promising physicochemical and stabilization attributes for application in EOR.

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Bronchobiliary fistula is a very rare complication of liver abscess. It presents with biliptysis (bile in cough), and chronic cough. Here we present a case of intractable biliptysis from a bronchobiliary fistula secondary to a liver abscess with biliary obstruction.

Synthesis, characterization, physical and thermodynamic properties of a novel anionic surfactant derived from Sapindus laurifolius.

The present study deals with the synthesis, characterization, physical and thermodynamic properties of a novel anionic surfactant derived from Sapindus laurifolius for its potential application against conventional non-biodegradable surfactants. The synthesized surfactant was characterized by FTIR, GC-MS, EDX and FE-SEM analyses. The surfactant showed good thermal stability at different temperatures as obtained from TGA studies. Critical micelle concentration (CMC) values were obtained by surface tensiometry measurements. DLS studies revealed the micelle structures of the CMC aggregates at higher concentrations. Low interfacial tension values were obtained at the oil-aqueous interfaces for surfactant solutions. The effect of temperature on the interfacial behaviour was also investigated. Thermodynamic studies showed that adsorption was more favoured in comparison to micellization for all systems. Foam stability studies were performed as a function of time and concentration by the Bartsch method. The surfactant also formed stable emulsions at concentrations near the CMC value. A comprehensive assessment of the thermal, interfacial, foaming and emulsifying properties of the soap-nut-based surfactant provides grounds for potential application in a wide range of industries.

A case of choledochoduodenal fistula - an unusual case report.

Choledochoduodenal fistula (CDF) is an abnormal communication between the choledochus and the duodenum, accounts for 5-25% of all internal biliary fistulas. Here, we report a case of CDF secondary to chronic duodenal ulcer who presented with cholangitis. CDF is suspected in case of pneumobilia, and surgery is recommended for refractory cases.

Malignant Tumor at D-4 Mimicking Wilkie's Syndrome.

Primary carcinoma of the duodenum is rare. Here we present a case of megaduodenum due to duodenal adenocarcinoma mimicking Wilkie's syndrome which was managed by resection and anastomosis.

Ileosigmoid knot.

Ileosigmoid knotting, also known as compound volvulus or double Volvulus, is a rare cause of acute intestinal obstruction. In this condition the ileum wraps around the base of the sigmoid colon and forms a knot. The condition is serious, generally progressing rapidly to gangrene of both ileum and sigmoid colon. Ileosigmoid knotting is an unusual entity in the West, but is comparatively common in certain African, Asian and Middle Eastern nations. Awareness of the condition is essential for prompt diagnosis and optimal management. This article will focus on the etiopathogenesis, presentation, diagnostic modalities, surgical interventions and outcome with review of articles and case reports published till date.

Isotope effects on the enzymatic and nonenzymatic reactions of chorismate.

The important biosynthetic intermediate chorismate reacts thermally by two competitive pathways, one leading to 4-hydroxybenzoate via elimination of the enolpyruvyl side chain, and the other to prephenate by a facile Claisen rearrangement. Measurements with isotopically labeled chorismate derivatives indicate that both are concerted sigmatropic processes, controlled by the orientation of the enolpyruvyl group. In the elimination reaction of [4-2H]chorismate, roughly 60% of the label was found in pyruvate after 3 h at 60 degrees C. Moreover, a 1.846 +/- 0.057 2H isotope effect for the transferred hydrogen atom and a 1.0374 +/- 0.0005 18O isotope effect for the ether oxygen show that the transition state for this process is highly asymmetric, with hydrogen atom transfer from C4 to C9 significantly less advanced than C-O bond cleavage. In the competing Claisen rearrangement, a very large 18O isotope effect at the bond-breaking position (1.0482 +/- 0.0005) and a smaller 13C isotope effect at the bond-making position (1.0118 +/- 0.0004) were determined. Isotope effects of similar magnitude characterized the transformations catalyzed by evolutionarily unrelated chorismate mutases from Escherichia coli and Bacillus subtilis. The enzymatic reactions, like their solution counterpart, are thus concerted [3,3]-sigmatropic processes in which C-C bond formation lags behind C-O bond cleavage. However, as substantially larger 18O and smaller 13C isotope effects were observed for a mutant enzyme in which chemistry is fully rate determining, the ionic active site may favor a somewhat more polarized transition state than that seen in solution.

Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor.

The highest affinity inhibitor for chorismate mutases, a conformationally constrained oxabicyclic dicarboxylate transition state analogue, was modified as suggested by computational charge optimization methods. As predicted, replacement of the C10 carboxylate in this molecule with a nitro group yields an even more potent inhibitor of a chorismate mutase from Bacillus subtilis (BsCM), but the magnitude of the improvement (roughly 3-fold, corresponding to a DeltaDeltaG of -0.7 kcal/mol) is substantially lower than the gain of 2-3 kcal/mol binding free energy anticipated for the reduced desolvation penalty upon binding. Experiments with a truncated version of the enzyme show that the flexible C terminus, which was only partially resolved in the crystal structure and hence omitted from the calculations, provides favorable interactions with the C10 group that partially compensate for its desolvation. Although truncation diminishes the affinity of the enzyme for both inhibitors, the nitro derivative binds 1.7 kcal/mol more tightly than the dicarboxylate, in reasonable agreement with the calculations. Significantly, substitution of the C10 carboxylate with a nitro group also enhances the selectivity of inhibition of BsCM relative to a chorismate mutase from Escherichia coli (EcCM), which has a completely different fold and binding pocket, by 10-fold. These results experimentally verify the utility of charge optimization methods for improving interactions between proteins and low-molecular weight ligands.

Stereocontrol in organic synthesis using silicon-containing compounds. Studies directed towards the synthesis of ebelactone A.

Several approaches to the synthesis of ebelactone A 2 are described, culminating in the synthesis of the benzenesulfonate of 2-epi-ebelactone A 161. All the approaches were based on three fragments A, B and C, originally defined in general terms in, but eventually used as the aldehyde 72, the allenylsilane 3 and the aldehyde 139, respectively. They were joined, first B with C, and then B+C with A. In the main routes to fragments A and C, the relative stereochemistry was controlled by highly stereoselective enolate methylations 67-->67, 68-->69, and 135-->136, in each case anti to an adjacent silyl group, and by a highly stereoselective hydroboration of an allylsilane 137-->138, also anti to the silyl group. The hydroxyl groups destined to be on C-3 and C-11 were unmasked by silyl-to-hydroxy conversions 69-->70 and 138-->139 with retention of configuration. The stereochemistry created in the coupling of fragment B to C was controlled by the stereospecifically anti S(E)2' reaction between the enantiomerically enriched allenylsilane 3 and the aldehyde 139. The double bond geometry was controlled by syn stereospecific silylcupration 148-->151, and preserved by iododesilylation 151-->152 of the vinylsilane with retention of configuration, and Nozaki-Hiyama-Kishi coupling with the aldehyde 72 gave the whole carbon skeleton 153 of ebelactone A with the correct relative configuration, all of which had been controlled by organosilicon chemistry. In the steps to remove the superfluous allylic hydroxyl, an intermediate allyllithium species 156 abstracted the proton on C-2, and its reprotonation inverted the configuration at that atom. Other routes to the fragments A and C were also explored, both successful and unsuccessful, both silicon-based and conventional, and a number of unexpected side reactions were investigated.