Identification of new modulator of DNA repairing pathways based on natural product (±)-peharmaline A.

The complex heterogenic environment of tumour mass often leads to drug resistance and facilitate chemo insensitivity triggering more malignant phenotypes among cancer patients. Major DNA-damaging cancer drugs have been consistently proven unsuccessful in terms of elevating chemo-resistance. (±)-peharmaline A, a hybrid natural product isolated from seeds of Peganum harmala L. possesses significant cytotoxic activities. Herein, we have described the design, and synthesis of a novel library of close and simplified analogues around the anticancer natural product (±)-peharmaline A and investigated their cytotoxic activities, which led to the identification of three structurally simplified lead compounds exhibiting better potency than parent natural product. Among them, demethoxy analogue of peharmaline A was further investigated for its anticancer potential eliciting demethoxy analogue as potent DNA-damage inducing agent attenuating the expression of the proteins responsible for the DNA damage repair. Therefore, this demethoxy analogue warrants detailed investigations for the confirmations of the molecular mechanism-based studies responsible for its anticancer activity. ______________________________________________________________________________.

Identification of a Novel Series of Potent Organosilicon Mosquito Repellents.

Mosquito control by personal protection is one of the most efficient ways of curtailing deadly diseases such as malaria and dengue with the potential to save millions of lives per year. DEET (N,N-diethyl-3-methyl benzamide) is currently considered as the gold standard for mosquito repellents, being used for the past several decades. Control by DEET, however, is being threatened by emerging resistance among mosquitoes. To address this concern and also to improve protection times, we synthesized a novel series of 25 silicon-containing acyl piperidines using acid-amine coupling protocol and tested their activity against Aedes aegypti in mosquito-repellent assays. Several compounds from this series appear to possess good mosquito-repellent properties. Most notably, at 0.5 mg/cm2 concentrations, the mean protection time for NDS100100 was 756 min, which was higher than that of DEET (616 min). The details of design, synthesis, and biological evaluation are discussed herein.

Development and Characterization of Biocompatible Membranes from Natural Chitosan and Gelatin for Pervaporative Separation of Water-Isopropanol Mixture.

Natural polymers have attracted a lot of interest in researchers of late as they are environmentally friendly, biocompatible, and possess excellent characters. Membranes forming natural polymers have provided a whole new dimension to the separation technology. In this work, chitosan-gelatin blend membranes were fabricated using chitosan as the base and varying the amount of gelatin. Transport, mechanical, and surface characteristics of the fabricated membranes were examined in detail by means of the characterizing techniques such as Fourier transform infrared spectroscopy, differential scanning colorimetry, wide angle X-ray diffraction, scanning electron microscope, and thermogravimetric analysis. In order to analyze the water affinity of the developed blend chitosan-gelatin membranes, the percentage degree of swelling was examined. Out of the fabricated membranes, the membrane loaded with 15 mass% of gelatin exhibited the better pervaporation performance with a pervaporation separation index value of 266 at 30 °C for the solution containing 10% in terms of the mass of water, which is the highest among the contemporary membranes. All the fabricated membranes were stable during the pervaporation experiments, and permeation flux of water for the fabricated membranes was dominant in the overall total permeation flux, signifying that the developed membranes could be chosen for efficient separation of water-isopropanol mixture on a larger scale.

Fabrication and Physicochemical Study of B2SA-Grafted Poly(vinyl Alcohol)-Graphene Hybrid Membranes for Dehydration of Bioethanol by Pervaporation.

Tetraethylorthosilicate (TEOS)-crosslinked poly(vinyl alcohol) (PVA) solution was prepared and treated with benzaldehyde 2 sulphonic sodium salt acid (B2SA) for sulfonation. Different contents of graphene were incorporated into B2SA-grafted PVA-TEOS hybrid membrane to improve the membrane stability, mechanical strength, and overall pervaporation performance of the membranes. Membranes were fabricated using the casting technique. Developed membranes were then analyzed for their physicochemical changes by means of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscope (SEM), wide-angle X-ray diffraction (WAXD), thermogravimetric analysis (TGA), contact angle analysis (CA), and mechanical strength. The lower d-spacing value observed in WAXD was evidence for the decreased inter-chain distance between the polymer chains. DSC exhibited the enhanced thermal stability of the developed membranes compared to the plane PVA membrane with enhancement in Tg value (106 °C), which was well above the pervaporation experimental temperature. Incorporation of graphene induced higher mechanical strength to the fabricated membranes. Further, the membranes were tested for the pervaporation separation of bioethanol. All the membranes were stable throughout the pervaporation studies, with M-2 G showing the total permeation flux of 11.66 × 10-2 kg/(m2 h) at 30 °C.

Novel fabrication of PSSAMA_Na capped silver nanoparticle embedded sodium alginate membranes for pervaporative dehydration of bioethanol.

Polystyrene-4-sulfonic acid co maleic acid sodium salt (PSSAMA_Na) capped silver nanoparticle (Ag_Np) embedded sodium alginate (Na-Alg) nanocomposite membranes have been developed to improve the pervaporation (PV) dehydration of bioethanol. The effect of PSSAMA_Na capped Ag_Nps on the micro-morphology, physicochemical properties and separation performance of the derived membranes was analyzed as a function of temperature at the azeotropic composition of the bioethanol-water mixture. WAXD analysis shows a decrease in crystalline domains with the increase in PSSAMA_Na capped Ag_Nps content and confirms the presence of Ag_Nps. DSC analysis demonstrated that the hydrophilic nature enhances as the PSSAMA_Na capped Ag_Nps content increases in the membrane matrix. Further, both total permeation flux and separation selectivity were increased with an increase in PSSAMA_Na capped Ag_Nps content. The results revealed that the membrane with 3 mass% of PSSAMA_Na capped Ag_Nps exhibited the highest permeation flux (13.40 × 10-2 kg m-2 h-1) and separation selectivity (11 406) at 30 °C which indicate its better PV performance. The total permeation flux and permeation flux of water values were close to each other, which confirms that the membranes can be efficiently used to remove the water from azeotropic aqueous bioethanol.

Evaluating antimalarial efficacy by tracking glycolysis in Plasmodium falciparum using NMR spectroscopy.

Glucose is an essential nutrient for Plasmodium falciparum and robust glycolytic activity is indicative of viable parasites. Using NMR spectroscopy, we show that P. falciparum infected erythrocytes consume ~20 times more glucose, and trophozoites metabolize ~6 times more glucose than ring stage parasites. The glycolytic activity, and hence parasite viability, can be measured within a period of 2 h to 5 h, using this method. This facilitates antimalarial bioactivity screening on ring and trophozoite stage parasites, exclusively. We demonstrate this using potent and mechanistically distinct antimalarial compounds such as chloroquine, atovaquone, cladosporin, DDD107498 and artemisinin. Our findings indicate that ring stage parasites are inherently more tolerant to antimalarial inhibitors, a feature which may facilitate emergence of drug resistance. Thus, there is a need to discover novel antimalarial compounds, which are potent and fast acting against ring stage parasites. The NMR method reported here can facilitate the identification of such molecules.

Targeted Phenotypic Screening in Plasmodium falciparum and Toxoplasma gondii Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules.

The Malaria Box collection includes 400 chemically diverse small molecules with documented potency against malaria parasite growth, but the underlying modes of action are largely unknown. Using complementary phenotypic screens against Plasmodium falciparum and Toxoplasma gondii, we report phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation, and egress or host invasion, providing hitherto unavailable insights into the possible mechanisms affected. First, the Malaria Box library was screened against tachyzoite stage T. gondii and the half-maximal effective concentrations (EC50s) of molecules showing ≥80% growth inhibition at 10 µM were determined. Comparison of the EC50s for T. gondii and P. falciparum identified a subset of 24 molecules with nanomolar potency against both parasites. Thirty molecules that failed to induce acute growth inhibition in T. gondii tachyzoites in a 2-day assay caused delayed parasite death upon extended exposure, with at least three molecules interfering with apicoplast segregation during daughter cell formation. Using flow cytometry and microscopy-based examinations, we prioritized 26 molecules with the potential to inhibit host cell egress/invasion during asexual developmental stages of P. falciparum. None of the inhibitors affected digestive vacuole integrity, ruling out a mechanism mediated by broadly specific protease inhibitor activity. Interestingly, five of the plasmodial egress inhibitors inhibited ionophore-induced egress of T. gondii tachyzoites. These findings highlight the advantage of comparative and targeted phenotypic screens in related species as a means to identify lead molecules with a conserved mode of action. Further work on target identification and mechanism analysis will facilitate the development of antiparasitic compounds with cross-species efficacy. IMPORTANCE The phylum Apicomplexa includes many human and animal pathogens, such as Plasmodium falciparum (human malaria) and Toxoplasma gondii (human and animal toxoplasmosis). Widespread resistance to current antimalarials and the lack of a commercial vaccine necessitate novel pharmacological interventions with distinct modes of action against malaria. For toxoplasmosis, new drugs to effectively eliminate tissue-dwelling latent cysts of the parasite are needed. The Malaria Box antimalarial collection, managed and distributed by the Medicines for Malaria Venture, includes molecules of novel chemical classes with proven antimalarial efficacy. Using targeted phenotypic assays of P. falciparum and T. gondii, we have identified a subset of the Malaria Box molecules as potent inhibitors of plastid segregation and parasite invasion and egress, thereby providing early insights into their probable mode of action. Five molecules that inhibit the egress of both parasites have been identified for further mechanistic studies. Thus, the approach we have used to identify novel molecules with defined modes of action in multiple parasites can expedite the development of pan-active antiparasitic agents.

Route to Benzimidazol-2-ones via Decarbonylative Ring Contraction of Quinoxalinediones: Application to the Synthesis of Flibanserin, A Drug for Treating Hypoactive Sexual Desire Disorder in Women and Marine Natural Product Hunanamycin Analogue.

A simple and practical method to access a variety of benzimidazol-2-ones is reported here. A series of N-alkyl-substituted benzimidazol-2-ones were synthesized by decarbonylative ring contraction starting from corresponding quinoxalinediones for the first time. The utility of the method has been demonstrated by synthesizing recently approved controversial drug flibanserin (Addyi) and a urea analogue of marine antibiotic natural product hunanamycin-A.