SYNTHESIS, BIOLOGICALEVALUATION AND MOLECULAR MODELING OF ARYLFURANS AS POTENTIAL TRYPANOTHIONE REDUCTASE INHIBITORS. Trypanosoma cruzi is a protozoan parasite that causes a severe disease (Chagas’disease) in Central and South America. The currently available chemotherapeutic agents against this disease are still inadequate. The enzyme trypanothione reductase (TR) is considered a validated molecular target for the development of new drugs against this parasite. In this regard, a series of arylfurans based on 2,5-bis-(4-acetamidophenyl)furan was synthesized and tested for their in vitro inhibitory activity against TR. Molecular modeling studies of putative enzyme-inhibitor complexes revealed a possible mechanism of interaction. From synthesized compounds, a benzylaminofuran derivative was found to be more active than the lead compound.
26.Banerjee, S.; Veale, E. B.; Phelan, C. M.; Murphy, S. A.; Tocci, G. M.; Gillespie, L. J.; Frimannsson, D. O.; Kelly, J. M.; Gunnlaugsson, T., Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents. Chemical Society Review. 2013, 42 (4), 1601-18. 27.Wu, A.; Xu, Y.; Qian, X.; Wang, J.; Liu, J., Novel naphthalimide derivatives as potential apoptosis-inducing agents: design, synthesis and biologicalevaluation. European Journal of Medicinal Chemistry. 2009, 44 (11), 4674-80.
Within the last time to solve the questions of prolonged activity of silver, to protect it from fast inactivation, to increase its biological availability and efficiency some other approaches based on complex formations of silver together with ligands and stabilization of silver with polymers were used /2-5/. As an example a new domestic product of colloid silver named poviargol can be mentioned. In this product to stabilize the colloid particles instead of protein hydrolizates the polymer of medical assignment polyvinilpirrolydone (entherodez, hemodez) is used /16/. Poviargol is produced in the form of a powder. It is used ТЧ ЭСО ПШЫЦ ШП аКЭОЫ ЬШХЮЭТШЧЬ аСТМС КЫО ЩЫОЩКЫОН ЭОЦЩШЫО. TСО ЬТЦТХКЫ КЩЩЫШКМС ЛКЬОН ШЧ МШЦЩХОб ПШЫЦКЭТШЧ КЧН stabilization of silver with polymer was used to produce another product named argovit.
ration into circulating red blood cells of mice made polycythemic by exposure to reduced atmospheric pressure. Although this bioas- say is normally sensitive, precise and specif- ic, the procedure has a number of drawbacks in that it requires the use of a radioisotope and elaborate animal preparation. Currently, the normocythemic mouse bioassay is per- formed in normal animals with single (13- 15) or multiple injections (16-18) and the biological activity of rhEPO is measured by the stimulation of reticulocyte production (3,16-18). Bioassays, in particular that in- volving a single injection into normocythemic mice, have been widely applied in standard- ization studies and in the potency evaluation of pharmaceutical preparations (13,15,19); however, although they are usually robust, some improvement is needed with regard to response variability and accuracy, most im- portantly when assessing the potency of com- mercial rhEPO batches from various sources (13,14).
A series of thirty-two isoniazid derivatives have been evaluated for their activity against four human cancer cell lines with potent cytotoxicity (IC50 ranging from 0.61 to 3.36 μ g/mL). The structure-activity relationship (SAR) analysis indicated the number, the positions, and the types of substituents attached to the aromatic ring as being critical factors for the biological activity. Briefly, we observed that the presence of a hydroxyl group on the benzene ring plays an important role in the anticancer activity of this series, especially when it is located in ortho-position. Among the thirty-two compounds, three displayed good cytotoxic activity when compared to the reference drug doxorubicin and are thus being considered leading compounds of this new class.
Crotalus durissus terriicus snake venom, vacuum dried and stored at 4°C, was obtained from specimens kept in the serpentarium of the Center for the Studies of Venoms and Venomous Animals (CEVAP), São Paulo state, Brazil. Sephadex G-75, Benzamidine Sepharose 6B, C2/ C18 column for RP/HPLC and molecular weight markers were purchased from Amersham Life Science Inc (Sweden). he H-D-Phe-pipecolyl- Arg-pNA.2HCl (S-2238) and H-D-Ile-Pro- Arg-pNA.2HCl (S-2288) substrates came from Chromogenix (Italy). All other reagents used for chemical and biological characterization were of analytical grade and purchased from Sigma Chemical Co (USA). he plasma was obtained from healthy donors, aged between 18 and 42 years, kindly provided by the Botucatu Medical School Blood Bank, São Paulo, Brazil.
After the above mentioned optimized methodology the second part of this work is dedicated to the biological activity of 3HQ and its derivatives. Various synthetic modifications have been made to introduce specific chemical group keeping the 3HQs core structure. Several compounds with different properties were synthesized and important biological studies were performed on 4-carboxamide-3HQ derivatives showed interesting biological activity as a potential anticancer lead molecule. Additionally, based on the that 3HQs can complex metallic centers and been an isoster of glycine, we hypothesized that 3HQ derivatives could be a useful platform to design new modulators of human phenylalanine hydroxylase (hPAH), the enzyme responsible by the genetic disease phenylketonuria. The new hPAH modulators were simply prepared based on ring-expansion reaction of isatins with NHS-diazoacetate catalysed by di-rhodium(II) complexes yielding 4-Carboxamide-3HQs in good-to- excellent yields. The 7-trifluoromethyl-4-carboxamide-3HQs 134, was identified as the most efficient hPAH modulator, with an apparent binding affinity nearly identical to the natural allosteric activator L-Phenylalanine.
15 morphological alterations already mentioned above (Elmore, 2007). A noteworthy concept to keep in mind is that once activated, cells seemingly become committed to a programmed cell death. At the risk of being over simplistic the extrinsic pathway, as the name suggests, is activated by the binding of extracellular death ligands, such as FasL (fatty acid synthetase ligand) or tumour necrosis factor- α (TNFα), to their respective transmembrane death receptors (Wong, 2011). The family of transmembrane death receptors is vast including more than 20 proteins with a broad range of biological functions (Ouyang et al., 2012; Schulze-bergkamen and Krammer, 2004), however the best described and more extensively studied are type 1 TNF receptor (TNFR1) and a related protein Fas (CD95- FasL receptor) (Schulze-bergkamen and Krammer, 2004; Wong, 2011). Upon ligation to their cognate ligands, receptor trimerization occurs as well as clustering of death domains and the recruitment of adaptor proteins such as Fas-associated death domain (FADD) or TNFR1-associated death domain (TRADD) which in turn form a protein complex known as the death-inducing signalling complex (DISC) (Fulda and Debatin, 2006; Wong, 2011). Once formed this protein complex is responsible for the oligomerisation of pro-caspase-8 leading to its activation through self-cleavage. In turn caspase-8 can proteolytically activate downstream caspase effectors such as caspase-3 and caspase-7, or in other situations it can promote the activation of BH3-only protein BID (BH3- interacting domain death agonist) through crosstalk with the intrinsic pathway. After proteolytic activation by caspase-8, the truncated BID induces mitochondrial outer membrane permeabilisation (MOMP) by the formation of transmembrane BAX-BAK channels (BAX-Bcl-2-associated X protein), consequently causing the release of cytochrome c and assembly of the apoptosome (Figure 1.7). The last one is multi-protein complex, comprised by 7 molecules of apoptotic protease-activating factor-1 (Apaf-1), caspase-9 and cytochrome c that binds to the C-terminal region of Apaf-1. Together this complex is responsible for further amplifying the apoptotic signal in the intrinsic pathway (Taylor et al., 2008; Fulda and Debatin, 2006).
In the past few decades, medicinal chemistry researchers have mainly focused on the introduction of various side chains onto the aromatic ring core of xanthone in attempts to improve its bioactivity; however, little attention was paid to the structural modifications and anticancer activities of benzoxanthone, which possesses an extended π-system. Considering that a pharmacophore might im- prove its physicochemical and biological activities by the introduction of a nitro- gen-containing side chain 17 and the structure of 1,3-dihydroxybenzoxanthone, in the herein reported study, a series of novel benzo[b]xanthone derivatives with terminal amines linked by different carbon spacers were prepared and their effect on the growth of five human cancer cell lines, i.e., Hep-G2, BEL-7402, HeLa, MGC-803 and CNE, evaluated.
Malaria remains a major public health problem, especially in subtropical regions. This endemic disease is caused by parasitic protozoans that belong to the Plasmodium type and people who get malaria are typically very sick with high fevers, shaking chills, and flu-like symptoms. Approximately 3.2 billion people worldwide are at risk of being infected and develop this disease. The highest risk is in the sub-Saharan Africa region where approximately 80 % of cases and 90 % of deaths occurs, mostly in children under five years and in pregnant women. The rise and spread of the resistance of Plasmodium falciparum malaria to chloroquine, sulfadoxine- pyrimethamine and artemisinin as well as the resistance of P. falciparum malaria vectors to pyrethroids (insecticides used to prevent malaria in endemic regions), presents a serious challenge, especially in developing countries. Therefore it is imperative and crucial the design of new antimalarial drugs. Medicinal plants constitute a promising source of new drugs and there is now a real worldwide interest in antiplasmodial plants. Ellagic acid is a polyphenol found in various plant products, whose main biological activities include antioxidant, anticarcinogenic, antimicrobial, anti-inflammatory and antiplasmodial effect. This compound has an in vitro IC 50 between 100 and 300 nM against several Plasmodium falciparum strains,
From ancient times, human beings strive to discover the cure of diseases that affect them. Before the twentieth century, they used to treat diseases by rudimentary techniques such the use of medicinal herbs and potions, but the medicinal chemistry born in the mid-nineteenth century with the first serious efforts to isolate and purify the pure chemicals responsible for the medicinal properties (active principles) of remedies. Since then, it is possible to obtain many naturally occurring drugs and determine their structures (Figure 1.1.). 2,3 Nowadays, with the advances in chemical and biological
In this context, several heterocyclic systems with five-membered rings fused to a benzene nucleus play an important role on designing of new drugs, since they display an interesting and diversified pharmacological profile. In particular, 1,3-benzoxathiol-2-one and its derivatives have been reported as important pharmacophores that exhibit antibacterial, antimycotic, antioxidant, antitumor, and anti-inflammatory activities [5–8]. In 2011, our research group has published the first review article highlighting the main aspects of the chemistry and biological properties of 1,3-benzoxathiol-2-ones .
Schiff bases are the significant compounds owing to their wide range of biological activities and industrial applications. They have been found to have the pharmacological deeds such as antimalarial, antibacterial, antifungal, anticancer, antimicrobial activity 1-8 , antitubercular, anti-inflammatory, anti-inflammatory activity 9-10 , antitumor activity 11 , antikinetoplastid antimitotic activity 12 and anticonvulsant activity 13 . Schiff bases are the compounds containing azomethine group (-HC=N-) formed by condensation of a primary amine with an active carbonyl compound 14 . Sulfonamide derivatives have been subject to thorough studies where a wide diversity of those derivatives have been prepared and used in various biological and pharmacological fields. Schiff bases are among the most studies sulfonamide derivatives which have been used for several biological application 15-16 . These types of derivatives are very important because of their varied structures and biological activities 17-19 . The present work is oriented towards synthesis of some Schiff bases of sulfonamides by condensing 4-amino benzene sulfonamide 20 , 2-amino benzene sulfonamide with different aromatic aldehydes in the presence of glacial acetic acid and ethanol at 50-60°C (Scheme 1). The Colletotrichum
The “bacuri” (Platonia insignis Mart., Clusiaceae) is a native tropical fruit from the Brazilian Amazon and Northeast Regions. Its seeds are used to treat inflammatory diseases, diarrhea and skin problems in traditional medical practices. Regarding its widespread medicinal uses, it is important to evaluate the biological and toxicological potential of this species. This way, the aim of this study was to investigate the in vitro cytotoxic and immunomodulatory effects of the hexanic extract of P. insignis seeds, as well as its in vivo acute oral toxicity. The biologicalevaluation was performed by the determination of cyto- toxic (MTT and hemolysis assay) and immunomodulatory (phagocytic capacity, lysosomal volume and nitrite production) activities of EHSB in murine peritoneal macrophages. In addition, the oral acute tox- icity was evaluated using female Wistar rats treated with EHSB (2.0 g/kg), in accordance with the OECD 423 Guideline. The EHSB showed low toxicity for macrophages in the MTT test (CC 50 value: 90.03 g/ml), as well as for erythrocytes, which caused only 2.5% hemolysis at the highest concentration. A strong immunomodulatory activity was observed by a markedly increase of the NO production, phagocytic abil- ity and lysosomal volume. On the other hand, it was not observed deaths or changes in the clinical and behavioral parameters in the toxicological evaluation. This manner, the present study contributes to the knowledge about the immunomodulatory and toxicological properties of the P. insignis. This may provide perspectives for the evaluation and development of effective and safe phytomedicines created from the Brazilian local biodiversity.
Following ecdysis, ﬁ fth-instar nymphae of male R. prolixus were starved for 25 days. Insects were then submitted to three different approaches. In the control group I insects were only fully engorged on citrated whole human blood. Doses of 0.5 μL and 1.0 μL per insect of the crude P. spicatus essential oil were used for the topical treatment and applied directly to the ventral surface of the abdomen immediately after feeding. Feeding treatment with P. spicatus oil was performed by adding different amounts of the crude essential oil to reach ﬁ nal concentrations of 5 μL and 10 μL /mL to the blood meal. To compare the effect of blood meal alone on the moult process during feeding treatment assays, partially-fed insects (control II) had a deliberated interrupted feeding in such a way to ingest the same amount of human blood than P. spicatus-fed insects. Except for these groups, only fully engorged insects were used throughout the experiments. The biologicalevaluation of the different treatments were recorded by weight of ingested blood, toxicity (i.e., 24 h mortality), intermoulting period (range), ecdysis and paralysis, which was determined by the absence of response to checking withdrawal reﬂ ex after application of a delicate pressure to the legs with forceps and watching the capacity of the antennae to be extended as well as by the absence of nymph movement (Garcia et al., 1990). All experiments were repeated at least in triplicate with batches of 50 insects.
The only drugs approved for the treatment of Chagas disease, nifurtimox and benznidazole, present toxic side effects and limited efficacy in the chronic stage of the disease, which highlight the need for new drugs. Amongst the different molecular drug targets discovered in the parasite, Trypanosoma cruzi trans-sialidase (TcTS) has been considered crucial in the recognition and invasion of host cells. Hence, we report the efficient synthesis and biologicalevaluation (TcTS inhibition and antitrypanosomal activities) of some galactose-containing triazol-arylsulfonamides via microwave-assisted Cu(I) 1,3-dipolar azide-alkyne cycloaddition (CuAAC) based on azide benzenesulfonamides and a galactose-derived alkyne as precursors. Most of the compounds tested against TcTS showed moderate to weak inhibition (40%-15%), except one of the compounds (81%). Regarding the antitrypanosomal assay, some compounds [(IC 50 70.9 µM) and (IC 50 44.0 µM)]
1,2,3-triazole moiety does not occur in nature, although synthetic molecules containing 1,2,3-triazole have shown several biological activities including antibacterial, herbicidal, fungicidal, antiallergic and anti-HIV 2,3 . Literature has recently reported the preparation of triazole derivatives linked to carbohydrates and biologicalevaluation of their glicoconjugates, have been shown to stand out as HIV reverse transcriptase (HIV-RT) inhibitors 1 , anti- trypanosomal agents, 2,4 inhibitors of α-glucosidases, 3,5 antitubercular activity 6,7 and antitumor agents 4,8 .
Our data, as well as the observations discussed above, underscore the importance of adequate controls for the evaluation of the biological roles of nitric oxide. On the basis of these data, we propose that the use of L- arginine analogues as probes of nitric oxide synthase activity should be controlled by at least 3 of the 4 following procedures: 1) reversal of the observed analogue effects by excess L-arginine; 2) if L-arginine reverses the blockade, it should be proved that D- arginine does not reverse it; 3) observation of the effects of the D-analogue form; 4) observation of the effects of more than one blocking analogue. In addition, data should be preferably complemented with measure- ments of nitric oxide synthase activity or nitric oxide levels. In particular, our data document the role of procedures 3 and 4 (use of the D-analogues and use of more than one antagonist), which are simple, but rarely per- formed. These procedures should be par- ticularly considered when evaluating the vas- cular interactions of nitric oxide with reac- tive oxygen species, or when assessing puta- tive cytotoxic or cytostatic effects of nitric oxide.
P. chlamydosporia is a fungus highly utilized in the biological control of nematodes, especially the root-knot nematodes, as it is a fungus that parasitizes females and eggs, the later being the most vulnerable stage of this pathogen life cycle. P. chlamydosporia caused a decline in the number of M. javanica galls and eggs, in tomato plants (DALLEMOLE-GIARETTA et al., 2014) by 40% and 72.83%, respectively. In the current study, the M. incognita in tomato roots was treated with the P. chlamydosporia, and its effect was compared with the control, as reported often by different authors (BOURNE & KERRY, 1999; ATKINS et al., 2003). However, the efficiency of the fungus in parasitizing the eggs present in the soil is dependent on two factors: temperature and developmental stage of the embryo within the egg. The fungus undergoes rapid colonization which occurs in the stages of cell multiplication and embryo development, and the juveniles hatch at temperatures approaching 30°C; they escape before the egg mass is colonized, because the fungus does not attack the mobile adult nematodes (DALLEMOLE-GIARETTA et al., 2008). With respect to the temperature conditions observed at the time the experiments were carried out (mean