Dynamics of Drop Formation in the Presence of Interfacial Mass Transfer.

The dynamics of drop formation have been investigated in the presence of interfacial mass transfer through controlled flow visualization experiments. The mixtures of n-hexane (solvent) and acetone (solute) were used as a dispersed phase, having different initial compositions varying over a broad range. Drops were formed at the submerged position in the continuous phase (water) at the same operating flow conditions. The unsteady force balance model is developed to analyze the implications of the simultaneously occurring interfacial transfer of the solute on the formation dynamics in real time, and predictions are validated with experimental results. Based on initial compositions, the analysis of the transient drop shape shows a sharp transition in the drop formation regime. At lower initial solute concentrations, i.e., ϕ0 < 0.2, axisymmetric drop formation occurs and the interfacial solute transfer has negligible effects on the formation dynamics. Over an intermediate range of solute concentrations, i.e., 0.2 < ϕ0 < 0.5, Marangoni instability is triggered along the evolving interface, and therefore, the interface deformations and contractions occur during the drop formation. At ϕ0 = 0.5, the drop takes highly nonaxisymmetric shapes and remains away from equilibrium until its detachment from an orifice. For ϕ0 > 0.5, the spontaneous ejection of plumes of the solute results in the rapid generation of multiple droplets of smaller size. This work shows that higher solute concentration gradients not only lead to faster solute transport but also induce strong interfacial instability simultaneously. Thus, the coupled effects of transient change in composition and fluid properties govern the drop size and its formation time in such systems under non-equilibrium.

Direct amidation of acids in a screw reactor for the continuous flow synthesis of amides.

A simple and efficient solvent-free protocol for continuous flow synthesis of amides at room temperature is developed using easily available starting materials. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) was used as the reagent for the formation of an amide bond without using any metal catalyst or additives. A jacketed screw reactor when operated over a residence time of 30 300 s helped achieve almost complete conversion. This approach is extended for the synthesis of 36 derivatives and 2 bioactive molecules using different substrates having different aliphatic mono and di-acids as well as aromatic acids, including aromatic hetero-acid compounds and phenyl hydrazine. The target amide was scaled up to 100 g with an average 90% yield.

Insights into the Synthesis and Kinetics of Silver-on-Silica Core-Shell Particles.

In this study, a heterogeneous nucleation and growth model has been developed to explore the formation mechanism of silver-deposited silica core-shell particles based on the reaction kinetics. To validate the core-shell model, the time-dependent experimental data were quantitatively examined and in situ reduction, nucleation, and growth rates were estimated by optimizing the concentration profiles of reactants and deposited silver particles. Using this model, we also attempted to predict the change in the surface area and diameter of core-shell particles. The concentration of the reducing agent, metal precursor, and reaction temperature were found to have a strong influence on the rate constants and morphology of core-shell particles. Higher rates of nucleation and growth often produced thick, asymmetric patches that covered the entire surface, whereas lower rates produced sparsely deposited silver particles with a spherical shape. The result revealed that by simply tuning the process parameters and controlling the relative rates, the morphology of deposited silver particles and the surface coverage can be controlled while retaining the spherical shape of the core. The present study aims to offer comprehensive data pertaining to the nucleation, growth, and coalescence processes of core-shell nanostructures which will aid in the development and understanding of the principles that govern the formation of nanoparticle-coated materials.

Mitral Annulus Disjunction and Arrhythmic Mitral Valve Prolapse: Emerging Role of Cardiac Magnetic Resonance Imaging in the Workup.

Mitral valve prolapse is a commonly described entity with a highly variable and benign course. However, it is associated with ventricular arrhythmias and sudden cardiac death in a small subset of patients. Recent studies have yielded insight into myocardial mechanics and the causation of ventricular arrhythmias in these groups of patients. Mitral annular disjunction (MAD) characterized by detachment of mitral annulus from left ventricular myocardium is associated with morphological and functional remodeling of the left ventricular myocardium. Resultant fibrosis acts as a substrate of ventricular arrhythmia and sudden cardiac death. We present two such cases of arrhythmic mitral valve prolapse associated with MAD. Cardiac magnetic resonance imaging provides excellent morphological information and also helps in the assessment of fibrosis.

Multi-Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry.

Herein we report for the first time, an advanced continuous flow synthesis of the blockbuster Leishmaniasis drug miltefosine from simple starting materials by a sequence involving four steps of chemical transformation including a continuous mechanochemical step. First three reaction steps were performed in simple tubular reactors in a telescopic mode, while in the last step the product precipitated from the 3rd step was used for a continuous mechanochemical synthesis of miltefosine. When compared to a typical batch protocol that takes 15 h, miltefosine was obtained in 58 % overall yield in flow synthesis mode at the laboratory scale in a total residence time 34 min at synthesis rate of 10 g/hr, which is sufficient to treat 4800 patients per day.

Inkjet printing of silver nanowires on flexible surfaces and methodologies to improve the conductivity and stability of the printed patterns.

Silver nanowires (AgNWs) are known to be used for printing on rigid as well as flexible surfaces. Here we have developed a systematic approach for using AgNWs synthesized by the polyol method for printing on flexible surfaces using a simple inkjet printing method. Optimized ink formulation used in this work comprises a mixture of Ag NWs suspended in ethylene glycol directly taken after synthesis and isopropyl alcohol. Using such formulation saves time and loss of material while transferring to other solvents, which is the usual practice. The printed patterns demonstrate high conductivity and stability over many months, which can revolutionize the applications of functional nanomaterials in low-cost printed electronics. The importance of fragmentation of nanowires only to achieve specific aspect ratios, to facilitate easy jetting and to prevent clogging is demonstrated. Varied concentrations (10 mg mL-1 to 50 mg mL-1) of Ag NWs are used in ink formulations in order to print highly conductive patterns (resistance < 50 Ω sq-1) in a minimal number of passes. The same composition was also seen to facilitate simple and time-efficient nano-welding at room temperature, which improves the conductivity and stability of the printed patterns.

Aloe vera Compositions Used for Medicinal Applications: A Patent Review (2013-till 2020).

BACKGROUND: Aloe vera is a plant traditionally used for medicinal purposes. It is also used as a cosmetic. Aloe vera gel/extract/juice is used in hair care, moisturizing, cleansing, and thickening agent in formulations. Aloe vera gel is rarely used for burns, wounds, infections, and gastric diseases. OBJECTIVES: To study the patents filed recently and understand the trend in the application of Aloe vera for therapeutic purposes. METHODS: This patent review focuses on granted patents during the year 2013 to 2020. The patents were analyzed, and their therapeutic use was studied to assess the recent trends in Aloe vera formulations. RESULTS: Most of the patents studied in this article are based on skincare products. Out of those, the maximum patents are on moisturizing compositions. Most of the patents are found in US jurisdiction and a few in Europe and China. As there are certain restrictions on patenting inventions related to composition and natural products in various jurisdictions, patents are only found in a few jurisdictions. CONCLUSION: The trend of the use of Aloe vera is still towards cosmetic products. Also, Aloe vera is used in oral care composition, deodorant compositions, anti-inflammatory composition, vitamin compositions, antibiotic compositions, etc.

Isatin Hybrids and Their Pharmacological Investigations.

Hybridization is an important strategy to design molecules that can be effectively used to treat fatal diseases known to mankind. Molecular hybrids and their pharmacological investigations aided in discovering several potent isatin (Indole 2, 3 dione) derivatives with anti-HIV, antimalarial, antitubercular, antibacterial, and anticancer activities. Indole-2,3-dione and their derivatives have diverse pharmacological properties and have a prominent role in the discovery of new drugs. To understand the various approaches for designing new molecules based on isatin nucleus analysis of various pharmacophore hybrids, spacers/linkers between pharmacophores and isatin for hybridization and their biological activities are important. This review discusses the progress in developing isatin hybrids as biologically effective agents and their crucial aspects of design and structure-activity relationships.

Design, synthesis, and screening of sulfonylurea-derived NLRP3 inflammasome inhibitors.

Inflammasomes are multiprotein assemblies that produce robust inflammatory responses upon stimulation with pathogen- and/or danger-associated molecular patterns. Uncontrolled inflammasome activation has been linked to the pathophysiology of a wide array of disorders including life-threatening pathogenic infections, e.g., Francisella tularensis. There has been a great deal of interest in the development of small molecule inflammasome inhibitors. Using computational modeling based on chalcone derivatives, we have developed novel tertiary sulfonylurea compounds as inhibitors of the NLRP3 inflammasome. The polar enone functional alert of chalcone was replaced with a sulfonylurea scaffold while maintaining the relative positions of the two aromatic rings. These compounds were evaluated for their ability to inhibit NLRP3 and AIM2 inflammasome activation triggered by Francisella tularensis infection.

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform.

The multistep flow synthesis of complex molecules has gained momentum over the last few years. A wide range of reaction types and conditions have been integrated seamlessly on a single platform including in-line separation as well as monitoring. Beyond merely getting considered as 'flow version' of conventional 'one-pot synthesis', multistep flow synthesis has become the next generation tool for creating libraries of new molecules. Here we give a more 'engineering' look at the possibility of developing a 'unified multistep flow synthesis platform'. A detailed analysis of various scenarios is presented considering 4 different classes of drugs already reported in the literature. The possible complexities that an automated and controlled platform needs to handle are also discussed in detail. Three different design approaches are proposed: (i) one molecule at a time, (ii) many molecules at a time and (iii) cybernetic approach. Each approach would lead to the effortless integration of different synthesis stages and also at different synthesis scales. While one may expect such a platform to operate like a 'driverless car' or a 'robo chemist' or a 'transformer', in reality, such an envisaged system would be much more complex than these examples.

Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4.

NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, however, suggests that Nox4 plays a critical role in fibrosis, as well as a host of pathologies and diseases. These considerations led to a search for novel, small molecule inhibitors of this important enzyme. Ultimately, a series of novel tertiary sulfonylureas (23-25) was designed using pharmacophore modeling, synthesized, and evaluated for inhibition of Nox4-dependent signaling.

Insights in the Diffusion Controlled Interfacial Flow Synthesis of Au Nanostructures in a Microfluidic System.

Continuous segmented flow interfacial synthesis of Au nanostructures is demonstrated in a microchannel reactor. This study brings new insights into the growth of nanostructures at continuous interfaces. The size as well as the shape of the nanostructures showed significant dependence on the reactant concentrations, reaction time, temperature, and surface tension, which actually controlled the interfacial mass transfer. The microchannel reactor assisted in achieving a high interfacial area, as well as uniformity in mass transfer effects. Hexagonal nanostructures were seen to be formed in synthesis times as short as 10 min. The wettability of the channel showed significant effect on the particle size as well as the actual shape. The hydrophobic channel yielded hexagonal structures of relatively smaller size than the hydrophilic microchannel, which yielded sharp hexagonal bipyramidal particles (diagonal distance of 30 nm). The evolution of particle size and shape for the case of hydrophilic microchannel is also shown as a function of the residence time. The interfacial synthesis approach based on a stable segmented flow promoted an excellent control on the reaction extent, reduction in axial dispersion as well as the particle size distribution.

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic.

The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring, optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time scale of operation. This classification will cover the broader range in the multistep synthesis literature.

Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus.

In a previous study, twelve antimalarial compounds, amodiaquine (AQ) and derivatives, were shown to have potent anti-dengue viral (DENV) activity by using the stable DENV2 Renilla luciferase reporter replicon expressing BHK-21 cells, infectivity (plaque), and the qRT-PCR assays. In this study, we performed molecular modeling on these compounds to determine their stereo-electronic properties required for optimal antiviral activity. Based on the similarity of calculated stereo-electronic profiles, specifically the electrostatic potential profiles of the compounds, and in silico screening of related compounds from literature, we identified three additional compounds, Quinacrine (QC), Mefloquine (MQ), and GSK369796. Analysis of their antiviral activities indicated that all three compounds have high anti-DENV activity in the DENV2 replicon expressing cells with EC50 values of 5.30 ± 1.31 µM (QC), 3.22 ± 0.37 µM (MQ), and 5.06 ± 0.86 µM (GSK369796). The infectivity assays revealed the EC50 values of 7.09 ± 1.67 µM (QC), 4.36 ± 0.31 µM (MQ) and 3.03 ± 0.35 µM (GSK369796). The mode of action of these compounds is through inhibition of autophagy, thereby affecting DENV2 replication. Moreover, these compounds also showed antiviral activity against the rapidly emerging Zika virus (ZIKV) with EC50 values of 2.27 ± 0.14 µM (QC), 3.95 ± 0.21 µM (MQ), and 2.57 ± 0.09 µM (GSK369796).

Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 µM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 µM) compared to curcumin (IC50=12 µM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.

Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey.

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President's Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent.

1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription.

BACKGROUND AND PURPOSE: HIV-1 transcription is activated by the Tat protein which recruits the cyclin-dependent kinase CDK9/cyclin T1 to TAR RNA. Tat binds to protein phosphatase-1 (PP1) through the Q(35) VCF(38) sequence and translocates PP1 to the nucleus. PP1 dephosphorylates CDK9 and activates HIV-1 transcription. We have synthesized a low MW compound 1H4, that targets PP1 and prevents HIV-1 Tat interaction with PP1 and inhibits HIV-1 gene transcription. Here, we report our further work with the 1H4-derived compounds and analysis of their mechanism of action. EXPERIMENTAL APPROACH: Using the 1H4-PP1 complex as a model, we iteratively designed and synthesized follow-up libraries that were analysed for the inhibition of HIV-1 transcription and toxicity. We also confirmed the mechanism of action of the PP1-targeting molecules by determining the affinity of binding of these molecules to PP1, by analysing their effects on PP1 activity, disruption of PP1 binding to Tat and shuttling of PP1 to the nucleus. KEY RESULTS: We identified a tetrahydroquinoline derivative, compound 7, which disrupted the interaction of Tat with PP1. We further optimized compound 7 and obtained compound 7c, renamed 1E7-03, which inhibited HIV-1 with low IC50 (fivefold lower than the previously reported compound, 1H4), showed no cytotoxicity and displayed a plasma half-life greater than 8 h in mice. 1E7-03 bound to PP1 in vitro and prevented shuttling of PP1 into the nucleus. CONCLUSIONS AND IMPLICATIONS: Our study shows that low MW compounds that functionally mimic the PP1-binding RVxF peptide can inhibit HIV-1 transcription by deregulating PP1.

Continuous flow nitration in miniaturized devices.

This review highlights the state of the art in the field of continuous flow nitration with miniaturized devices. Although nitration has been one of the oldest and most important unit reactions, the advent of miniaturized devices has paved the way for new opportunities to reconsider the conventional approach for exothermic and selectivity sensitive nitration reactions. Four different approaches to flow nitration with microreactors are presented herein and discussed in view of their advantages, limitations and applicability of the information towards scale-up. Selected recent patents that disclose scale-up methodologies for continuous flow nitration are also briefly reviewed.

Methyl 2-bromo-3-(4-chloro-benzene-sulfonamido)-benzoate.

In the crystal structure of the title compound, C(14)H(11)BrClNO(4)S, the mol-ecules form inversion dimers with R(2) (2)(8) motifs through pairs of N-H⋯O hydrogen bonds. The benzene rings are not coplanar and subtend a dihedral angle of 66.27 (8)°. The carbomethoxy group makes a dihedral angle of 75.1 (1)° with the ring to which it is attached.

Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF.

Curcumin is the principal active ingredient found in turmeric (Curcuma longa), a plant used in traditional Asian diets and herbal medicines. It is known to have a wide range of biological actions including antidepressant-like effects which have been observed in stress-induced depression models. This study was designed to investigate the antidepressant potential of curcumin in a non-induced model of depression. Moreover, since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant effects of many drugs, we also evaluated the effects of curcumin on BDNF in the hippocampus. Adult male Wistar Kyoto (WKY) rats, a putative model of depression, were injected acutely or chronically (10d) with 50, 100, and 200mg/kg curcumin. Open field locomotor activity (OFLA) and forced swim test (FST), a measure of helplessness, were measured 1h after acute and 18-20h after last chronic injection. Results showed a dose-dependent reduction of immobility in the FST by curcumin in both acute and chronic studies, without any significant effect on OFLA. The effect of higher chronic curcumin dose in FST was still evident a week later. Chronic curcumin also resulted in a dose-dependent increase in hippocampal BDNF. This data provides evidence for an antidepressant-like effect of curcumin, possibly through increased neurotrophic activity, in the WKY model of depression, and support the notion that curcumin may prove an effective and lasting natural antidepressant.