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Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodium proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a–o) and carboxylic acids 10(a–b) for the inhibition of Plasmodium N-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. The designed compounds exhibited a glide score of −9.241 to −6.960 kcal/mol for PvNMT and −7.538 kcal/mol for PfNMT model proteins. Development of the synthesized compounds was established via NMR, HRMS and single crystal X-ray diffraction study. The synthesized compounds were evaluated for their in vitro antimalarial efficacy against CQ-sensitive Pf3D7 and CQ-resistant PfINDO lines followed by cell toxicity evaluation. In silico results highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate (9a) as a promising inhibitor with a glide score of −9.084 kcal/mol for PvNMT and −6.975 kcal/mol for PfNMT with IC50 values of 6.58 µM for Pf3D7 line. Furthermore, compounds 9n and 9o exhibited excellent anti-plasmodial activity (Pf3D7 IC50 = 3.96, 6.71 µM, and PfINDO IC50 = 6.38, 2.8 µM, respectively). The conformational stability of 9a with the active site of the target protein was analyzed through MD simulation and was found concordance with in vitro results. Thus, our study provides scaffolds for the development of potent antimalarials targeting both Plasmodium vivax and Plasmodium falciparum. Communicated by Ramaswamy H. Sarma

We herein report unsymmetrical coupling of 2-methylquinolines under the blue LED light conditions using iridium-based photocatalyst. This methodology represents the direct synthetic method for the ...

C. pareira L. is a centuries-old traditional medicinal plant utilized to treat various diseases like asthma, diarrhea, fever, heart disorders, snakebite, vomiting, malaria, pneumonia, dog bite, inflammation and abdominal pain. Globally, based on traditional knowledge, different parts of this plant are being used individually or in combination in various forms to manage malaria. However, the scientific investigation for validating the most effective part of this plant against malaria parasite has not been done. Therefore, current study aimed to evaluate in vitro antiplasmodial activity of extracts/fractions (whole plant) and decoctions from different parts (roots, stem, leaves and whole plant) of C. pareira against different strains of Plasmodium falciparum followed by antiplasmodial activity guided isolation and quantification of isoquinoline alkaloids in extracts/fractions and decoctions. All extracts/fractions/decoctions and molecules isolated from active fractions were investigated for antiplasmodial activity. Results showed that the chloroform fraction of whole plant was the most promising with IC50 (µg/mL) of 0.79 (Pf3D7) and 2.26 (PfINDO) followed by root decoction having IC50 (µg/mL) 10.22 (Pf3D7) and 7.7 (PfINDO). Among three isolated molecules, two bisbenzylisoquinoline alkaloids namely curine (2) [IC50 (µM) 1.46 (Pf3D7) and 0.51 (PfINDO)], and O,O-dimethylcurine (1) [IC50 (µM) 0.92 (Pf3D7) and 2.6 (PfINDO)], were found to be the most potent against P. falciparum strains. The antiplasmodial activity of chloroform fraction was further validated by the developed UPLC-DAD method, which showed the highest quantities of curine (2) (~107 mg/g) and O,O-dimethylcurine (1) (~15 mg/g) in this fraction. This study showed that the root decoction was more effective than decoctions of each of the other parts of the plant and whole plant hydroalcoholic extract. Further, for the first time, this study validates the traditional use of C. pareira whole plant to manage malaria, providing further opportunity to explore the tremendous structural and chemical diversity of isoquinoline alkaloids for antimalarial drug development.

Malaria continues to be a killer disease even in the modern world. Indeed, vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinine, Curine, MMV689758 (Bedaquiline), MMV1634402 (Brilacidin), and MMV688271 with PfINDO IC50 ≤ 1 µM were found to stall merozoite invasion by inhibiting IMC formation besides increasing oxidant levels in trophozoites. Bedaquiline pre-treated and washed healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in a mouse model of malaria.

Malaria continues to be a killer disease even in the modern world. Vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinin, Bedaquiline, MMV688271, Curine, and Brilacidin with PfINDO IC50 ≤ 1 µM were found to stall merozoites invasion by inhibiting IMC formation besides increasing ROS levels in trophozoites. Bedaquiline loaded healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in the mouse model of malaria.

Aconitum heterophyllum Wall. ex Royle is a traditionally important medicinal plant having numerous therapeutic actions as documented in Ayurveda. This plant is traditionally known for combating worm infestation, fever, respiratory tract disease, vomiting, diarrhoea, diabetes, skin disorders, anaemia, and joint disorders. Further, it has been used alone and in combination with other plants to prepare various anti-malarial formulations. However, there is no report on the assessment of its anti-plasmodial activity, and the metabolite(s) responsible for this activity.The main aim of this study was to conduct phytochemical investigation of A. heterophyllum roots for the preparation of extract, fractions, and isolation of pure molecules to identify active fractions/molecules responsible for the anti-plasmodial activity, and development of UHPLC-DAD based analytical method which can be used for the quantification of marker compounds in the extracts and fractions.Hydroalcoholic extract (1:1 v/v) and fractions (n-hexane, chloroform, ethyl acetate, n-butanol, and water) were prepared from the dried powdered roots of A. heterophyllum. Fractions were further subjected to silica gel column chromatography to isolate pure specialized secondary metabolites from this plant. All extracts, fractions, and pure molecules were evaluated against the chloroquine resistant Pf INDO and chloroquine sensitive Pf3D7 strains in culture for calculating their ICPhytochemical investigation of A. heterophyllum root led to the isolation of six specialized metabolites viz. 2-O-cinnamoyl hetisine (1), atisinium (2), 4-oxabicyclo [3.2.2] nona-1(7),5,8-triene (3), atisinium cinnamate (4), aconitic acid (5), and atisinium formate (6). Compound 1 is a new hetisine type diterpenoid alkaloid, compounds 4 and 6 are new counter ionic forms observed with atisinium ion, and compound 3 is being reported for the first time from this genus. Chloroform fraction was found to be the most active with ICThis study provides the scientific rationale for the traditional use of this plant in treating malaria. Further, this study revealed that the anti-malarial potential of this plant might be due to the presence of diterpenoid alkaloids.

Aconitum heterophyllum is a traditionally important medicinal plant having numerous therapeutic actions as documented in Ayurveda. This plant has been used alone as well as in combination with other plants for the preparation of different anti-malarial formulations. However, there is no report on the assessment of its anti-plasmodial activity, and the compound responsible for this activity. The main aim of this study was to conduct phytochemical investigation of A. heterophyllum roots for the preparation of extract, fractions and isolation of pure molecules to identify active fractions/molecules responsible for the anti-plasmodial activity, and development of UHPLC-DAD based analytical method which can be used for the quantification of marker compounds in the extracts and fractions. Hydro-alcoholic extract (1:1 v/v) and fractions (n-hexane, chloroform, ethyl acetate, n-butanol and water) were prepared from the dried powdered roots of A. heterophyllum. Fractions were further subjected to silica gel-based column chromatography to isolate pure specialized secondary metabolites from this plant. All extracts, fractions and pure molecules were evaluated against the chloroquine resistant Pf INDO and chloroquine sensitive Pf3D7 strains in culture for calculating their IC50 values. UHPLC-DAD based analytical method was also developed for the first time for the quantification and quality assessment of this commercially important Himalayan medicinal plant. Phytochemical investigation of A. heterophyllum root led to the isolation of six specialized metabolites named as 2-O-cinnamoyl hetisine (1), atisinium (2), 4-oxabicyclo [3.2.2] nona-1(7),5,8-triene (3), atisinium cinnamate (4), aconitic acid (5), and atisinium formate (6). Compound 1 is a new hetisine type diterpenoid alkaloid, compounds 4 and 6 are new counter ionic forms observed with atisinium ion, and compound 3 is being reported for the first time from this genus. Chloroform fraction was found to be the most active with IC50 (µg/mL) 1.01 (Pf INDO) and 1.32 (Pf3D7). The isolated molecule 2-O-cinnamoyl hetisine (1), a new diterpenoid alkaloid isolated from chloroform fraction, showed promising antiplasmodial activities with IC50 (µM) 1.92 (Pf INDO) and 10.8 (Pf 3D7). Activity of chloroform fraction was further validated by the developed UHPLC-DAD based method as the quantity of 2-O-cinnamoyl hetisine (1) was higher in the chloroform fraction (≅200 µg/mL) than in all other fractions (< 7µg/mL). Atisinium (2) and 2-O-cinnamoyl hetisine (1) were found to be the main marker compounds of this plant based on quantity and antiplasmodial activity, respectively. This study provides the scientific rational for the traditional use of this plant in treating malaria. Further, this study revealed that anti-malarial potential of this plant might be due to the presence of diterpenoid alkaloids.

The human malaria parasite, Plasmodium falciparum possesses unique gliding machinery referred to as the glideosome that powers its entry into the insect and vertebrate hosts. Several parasite proteins including Photosensitized INA-labelled protein 1 (PhIL1) have been shown to associate with glideosome machinery. Here we describe a novel PhIL1 associated protein complex that co-exists with the glideosome motor complex in the inner membrane complex of the merozoite. Using an experimental genetics approach, we characterized the role(s) of three proteins associated with PhIL1: a glideosome associated protein- PfGAPM2, an IMC structural protein- PfALV5, and an uncharacterized protein—referred here as PfPhIP (PhIL1 Interacting Protein). Parasites lacking PfPhIP or PfGAPM2 were unable to invade host RBCs. Additionally, the downregulation of PfPhIP resulted in significant defects in merozoite segmentation. Furthermore, the PfPhIP and PfGAPM2 depleted parasites showed abrogation of reorientation/gliding. However, initial attachment with host RBCs was not affected in these parasites. Together, the data presented here show that proteins of the PhIL1-associated complex play an important role in the orientation of P. falciparum merozoites following initial attachment, which is crucial for the formation of a tight junction and hence invasion of host erythrocytes., Author summary Invasion of Plasmodium merozoites into RBCs is a multistep process that involves initial attachment of merozoites to the RBC surface, their reorientation, and subsequent gliding into RBCs using glideosome machinery. The glideosome machinery lies between the plasma membrane and inner membrane complex (IMC) and consists of MyoA, its interacting protein; MTIP, gliding associated proteins (GAPs), and a Photosensitized INA labeled protein (PhIL1)-associated protein complex. Here, we demonstrate that the deletion of any of two components of the PhIL1-associated complex, PfPhIP or PfGAPM2, aborts merozoite reorientation and blocks their invasion into RBCs. The study thus provides new molecular and mechanistic insights into merozoite invasion of RBCs.

Herein, we have synthesized a series of lipophilic, halogenated-arylvinyl-1,2,4-trioxanes 8a–g (28 compounds) and assessed for their in vitro anti-plasmodial activity in Plasmodium falciparum culture using SYBRgreen-I fluorescence assay against chloroquine-resistant Pf INDO and artemisinin-resistant Pf Cam 3.1R539T (MRA-1240) strains. Alongside, the cell cytotoxic potential of 8a–g has also been determined against the HEK293 cell line in vitro. Out of twenty-eight halogenated-arylvinyl-1,2,4-trioxanes; ten analogues (8a2, 8a4, 8b2, 8b4, 8d4, 8e1, 8e2, 8e4, 8f2, and 8g4) have shown potent in vitro antiplasmodial activity with IC50 1M17 ) have demonstrated the strong virtual interaction.

The human malaria parasite, Plasmodium falciparum possess a unique mechanism of gliding motility guided by glideosome that powers its entry into insect and vertebrate hosts to facilitate its invasion and internalization within the targeted host cell. Photosensitized INA-labelled protein 1 (PhIL1) forms a novel protein complex that is associated with glideosome motor complex in the inner membrane complex of invasive merozoite. To establish the role of PfPhIL1 associated novel complex at asexual blood stages, we characterized three proteins associated with PhIL1: a glideosome associated protein- PfGAPM2, an IMC structural protein- PfALV5 and a previously uncharacterised protein - referred here as PfPhIP (PhIL1 interacting protein). GFP targeting and co-immunoprecipitation analysis confirmed that these proteins are part of a PhIL1 associated novel complex, which co-exists with the glideosomal complex. To know the functional significance of PhIL1 associated complex, transgenic parasites were generated for glmS mediated conditional knock-down of each of the three proteins. Parasites lacking PfPhIP or PfGAPM2 were unable to invade the RBCs. PfPhIP deficient parasites also showed defects in merozoite segmentation. PfPhIP and PfGAPM2 depleted parasites revealed abrogation of reorientation/gliding, although initial attachment with human RBCs was not affected in these knock-down parasites. Together, the data presented here shows that proteins of the PhIL1 associated complex play an important role in orientation of P. falciparum merozoites post initial attachment, which is crucial for formation of tight junction and hence invasion of host erythrocytes.

Steganography and cryptography are two major aspects of data security . In this paper we are going to provide the survey of different techniques of LSB based Steganography that used cryptography algorithms to secure sensitive information. Steganography is used to hide data and Cryptography is used to encrypt the data. Although cryptography and steganography individually can provide data security, every of them has a drawback. Drawback associated with Cryptography is that, the cipher text looks meaningless, so the unintended user can interrupt the transmission or make more careful checks on the information from the sender to the receiver. Drawback associated with Steganography is that when the presence of hidden information is revealed or even suspected, the message is become known[1].By combining these two methods we can solve both of the above problem. First we encrypt the data using any cryptography technique and then embed the encrypted text into the image. Steganography is the process which hides the presence of secure data during communication. On the other hand cryptography is encrypting and decrypting of secure data and information with a secrete key so that no one can be understand the message directly.

The craft of data stowing away has gotten much consideration in the ongoing years as security of data has turned into a major worry in this web time. As sharing of delicate data by means of a typical correspondence channel have become inevitable, Steganography techniques aimed at secretly hiding data in a multimedia carrier such as text, audio, image or video, without raising any suspicion of alteration to its contents. The original carrier is referred to as the cover object. In this paper, we proposed a mechanism of end user data security by means of image steganography technique using ECDH (Elliptic Curve Diffie–Hellman) algorithm for improving image quality while we hide data in image. Our proposed approach is simplified yet efficient algorithm that can be implemented for end user application that strictly enforces the data integrity over the communication channel. The performance of the proposed approach is measured in terms of time, memory, MSE and PSNR which was better improved from the previous approach in the similar parameters.

Bilateral hyperplasia of the coronoid process of the mandible is an unusual entity which often presents with limited mouth opening. Thorough clinical and radiographic examination can help in the diagnosis and the treatment planning of this condition. This article consists of a case report of two patients. The patient in each case, presented with a reduced mouth opening, and when subjected to further investigations, was diagnosed with bilateral coronoid hyperplasia.

A novel series of synthetic functionalized arylvinyl-1,2,4-trioxanes (8 a-p) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine-resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green-I fluorescence assay. Compounds 8 g (IC50 =0.051 μM; SI=589.41) and 8 m (IC50 =0.059 μM; SI=55.93) showed 11-fold and >9-fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC50 =0.546 μM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl-1,2,4-trioxanes (8 g and 8 m) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a-p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a, 8 h, 8 l, 8 m and 8 o (IC50 =1.65-31.7 μM; SI=1.08-10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC50 =100 μM), chloroquine (IC50 =100 μM) and artesunic acid (IC50 =9.85 μM; SI=0.76). In fact, the most active 4-naphthyl-substituted analogue 8 l (IC50 =1.65 μM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m, against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl-vinyl-1,2,4-trioxanes (8 a-p) has been shown to display dual potency as promising antiplasmodial and anticancer agents.

Introduction: The use of plants for treating diseases is as old as the human species. Medicinal plants have been a major source of therapeutic agents for alleviation and cure of diseases. Objectives: The objective of the study was to evaluate and compare the antifungal activity of garlic, cinnamon, lemongrass and tulsi in powder and oil form at different concentrations on Candida albicans. Materials and Methods: Powder and oil of garlic, cinnamon, lemongrass and Tulsi dissolved in inert solvent dimethyl formamide to obtain different concentration. Stock solution of different concentration was inoculated on Petri plates containing C. albicans and incubated at 30°C for 48 h. The inhibition zones were measured in millimeters using Vernier caliper. The collected data were analyzed using statistical test like mean value and one-way analysis of variance. Results: Maximum zone of inhibition for the C. albicans was 42 mm at concentrations of 50% for the oil of lemongrass; followed by cinnamon 40 mm, garlic 24 mm and tulsi 20 mm. The P value obtained 0.050, 0.040, 0.036 and 0.031 were found to be statically significant for C. albicans at 20%, 30%, 40% and 50% concentrations of the various oil preparations, respectively. The P value obtained 0.043, 0.033, 0.032 and 0.027 were found to be statically significant for C. albicans at 20%, 30%, 40% and 50% concentrations of various plant powder, respectively. Conclusions: Lemongrass and cinnamon oil shows best antifungal effect against C. albicans as compared to garlic and tulsi. Compared to powder preparations, the oil preparations are better to inhibit the growth and higher the concentrations, greater the zone of inhibition seen in all the plant extracts and in oil.

Power grids are evolving at an unprecedented pace due to the rapid growth of distributed energy resources (DER) in communities. These resources are very different from traditional power sources, as they are located closer to loads and thus can significantly reduce transmission losses and carbon emissions. However, their intermittent and variable nature often results in spikes in the overall demand on distribution system operators (DSO). To manage these challenges, there has been a surge of interest in building decentralized control schemes, where a pool of DERs combined with energy storage devices can exchange energy locally to smooth fluctuations in net demand. Building a decentralized market for transactive microgrids is challenging, because even though a decentralized system provides resilience, it also must satisfy requirements such as privacy, efficiency, safety, and security, which are often in conflict with each other. As such, existing implementations of decentralized markets often focus on resilience and safety but compromise on privacy. In this article, we describe our platform, called TRANSAX, which enables participants to trade in an energy futures market, which improves efficiency by finding feasible matches for energy trades, enabling DSOs to plan their energy needs better. TRANSAX provides privacy to participants by anonymizing their trading activity using a distributed mixing service, while also enforcing constraints that limit trading activity based on safety requirements, such as keeping planned energy flow below line capacity. We show that TRANSAX can satisfy the seemingly conflicting requirements of efficiency, safety, and privacy. We also provide an analysis of how much trading efficiency is lost. Trading efficiency is improved through the problem formulation, which accounts for temporal flexibility, and system efficiency is improved using a hybrid-solver architecture. Finally, we describe a testbed to run experiments and demonstrate its performance using simulation results.

Additional file 2. Quantitation of un-ruptured schizonts in anti-rPfeno antibody treated cultures at 48 h post antibody addition. Control samples had no schizonts. Data are expressed as percent of total Schizonts present at 24 h post antibody addition (see Fig. 3).