Source Of Novel Drugs Research Articles

Probing of Metabolites in Finely Powdered Plant Material by Direct Laser Desorption Ionization Mass Spectrometry

Natural products continue to serve as an important source of novel drugs since the beginning of human history. High-throughput techniques, such as MALDI-MS, can be techniques of choice for the rapid screening of natural products in plant materials. We present here a fast and reproducible matrix-free approach for the direct detection of UV active metabolites in plant materials without any prior sample preparation. The plant material is mechanically ground to a fine powder and then sieved through different mesh sizes. The collected plant material is dispersed using 1 μL solvent on a target plate is directly exposed to Nd:YAG 335 nm laser. The strategy was optimized for the analysis of plant metabolites after study of the different factors affecting the reproducibility and effectiveness of the analysis, including particle sizes effects, types of solvents used to disperse the sample, and the part of the plant analyzed. Moreover, several plant species, known for different classes of metabolites, were screened to establish the generality of the approach. The developed approach was validated by the characterization of withaferin A and nicotine in the leaves of Withania somnifera and Nicotiana tabacum, respectively, through comparison of its MS/MS data with the standard compound. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) techniques were used for the tissue imaging purposes. This approach can be used to directly probe small molecules in plant materials as well as in herbal and pharmaceutical formulations for fingerprinting development.

Spider peptide Phα1β induces analgesic effect in a model of cancer pain

The marine snail peptide ziconotide (ω-conotoxin MVIIA) is used as an analgesic in cancer patients refractory to opioids, but may induce severe adverse effects. Animal venoms represent a rich source of novel drugs, so we investigated the analgesic effects and the side-effects of spider peptide Phα1β in a model of cancer pain in mice with or without tolerance to morphine analgesia. Cancer pain was induced by the inoculation of melanoma B16-F10 cells into the hind paw of C57BL/6 mice. After 14 days, painful hypersensitivity was detected and Phα1β or ω-conotoxin MVIIA (10-100 pmol/site) was intrathecally injected to evaluate the development of antinociception and side-effects in control and morphine-tolerant mice. The treatment with Phα1β or ω-conotoxin MVIIA fully reversed cancer-related painful hypersensitivity, with long-lasting results, at effective doses 50% of 48 (32-72) or 33 (21-53) pmol/site, respectively. Phα1β produced only mild adverse effects, whereas ω-conotoxin MVIIA induced dose-related side-effects in mice at analgesic doses (estimated toxic dose 50% of 30 pmol/site). In addition, we observed that Phα1β was capable of controlling cancer-related pain even in mice tolerant to morphine antinociception (100% of inhibition) and was able to partially restore morphine analgesia in such animals (56 ± 5% of inhibition). In this study, Phα1β was as efficacious as ω-conotoxin MVIIA in inducing analgesia in a model of cancer pain without producing severe adverse effects or losing efficacy in opioid-tolerant mice, indicating that Phα1β has a good profile for the treatment of cancer pain in patients.

Ecological role and biotechnological potential of mangrove fungi: a review

Mangroves are inhabited by large number of fungal communities, known as manglicolous fungi. They include mostly marine fungi and small group of terrestrial fungi and can be categorized into saprophytic, parasitic, and symbiotic fungi. Fungi in mangrove environment play an important ecological role in decomposition of organic matter by production of variety of extracellular degradative enzymes such as cellulase, xylanase, pectinase, amylase, and so on. Such enzymes can be isolated from the mangrove fungi and harnessed for several biotechnological applications. Several bioactive metabolites are derived from mangrove fungi, specially from mangrove endophytic fungi, which are used in pharmaceutical and nutraceutical industries to produce antimicrobial, anticancer, antioxidant, antidiabetic, and other therapeutic agents. Besides, certain mangrove fungi also contribute toward production of biopesticides useful in control of plant diseases, while others produce microbial lipids used as potential feed stock for biodiesel production. In spite of immense ecological role and biotechnological potentials, mangrove fungi are not extensively studied. The present review provides information on diversity and ecological role of mangrove fungi along with their biotechnological potentials as source of novel drugs, enzymes, biodiesel, biopesticides, and many other applications.

Assessment of Secondary Metabolites from Marine-Derived Fungi as Antioxidant

Marine derived fungi are considered as a promising source of novel drugs due to their biodiversity and consequent chemo-diversity. Although marine microorganisms especially fungi are not well defined taxonomically, making this a promising frontier for the discovery of new medicines. This study focused on marine derived fungi as a model for bioactive exploration for new entities with anti-inflammatory and antioxidant capacity. Three in-vitro assays were used to investigate the bioactive antioxidant potentiality of fungal extracts. Thiobarbituric acid (TBARS),α,α-Diphenyl-β- picrylhydrazyl (DPPH) and NO assay are based on their total phenolic and flavonoid content of each extract group. Ch. globosum recorded the highest antioxidant activity (92.82%) in TBARS assay, while G. dankaliensis came first by recording 59.28% in DPPH assay in comparison with ascorbic acid (61.83%). In NO inhibition assay, N. oryzae showed 49.3% comparing with ascorbic acid (73.12%). From the preliminary result of our extracts, we can consider the marine derived fungi extracts as promising antioxidant and anti-inflammatory drug candidate.

Endophytic fungi from Combretum leprosum with potential anticancer and antifungal activity

The recent increase in human diseases and cancers requires new drugs to combat them. Sources have been found in rare microorganisms, those from extreme habitats, and from endophytes. In this study, the biological activity of endophytic fungi associated with the Brazilian medicinal plant Combretum leprosum was assessed. Cytotoxic and antiproliferative effects were evaluated using seven human cancer cells lines (HeLa, ECV304, B16F10, J744, P388, Jurkat and k562). In addition the minimum inhibitory concentration (MIC) against pathogenic human fungal was determined using four Candida species and the filamentous fungi Cryptococcus neoformans and Trichophyton rubrum. A compound from extracts of phylotype Aspergillus oryzae CFE108 exhibited the most significant cytotoxicity effect against histiocytic sarcoma J774 (IC50 of 0.80 μg mL−1), leukemia Jurkat (IC50 of 0.89 μg mL−1), bladder carcinoma ECV304 (IC50 of 3.08 μg mL−1) and cervical cancer HeLa (IC50 of 2.97 μg mL−1). The extract from phylotypes Fusarium oxysporum CFE177 displayed antifungal activity and inhibited the growth of Candida glabrata (4 μg mL−1) as well as that of C. neoformans and T. rubrum with the lowest MIC being 62.5 μg mL−1. In addition, the fractions from A. oryzae CFE108 showed marked morphological activity (rounding up) on endothelial cells (tEnd.1 cells), which is indicative of potential antivascular activity. Our results indicate that the endophytes associated with this medicinal plant may be a source of novel drugs.

Glycobiology: an untapped source of novel drugs

Glycobiology: an untapped source of novel drugs

English

Since ages, many plants have been used for preservative and medicinal purposes due to the presence of secondary metabo- lites referred as Phytochemicals. Phytochemicals are biologically active plant compounds having disease hampering capabilities and preservative action. The genus Ocimum contains more than 200 species of herbs and shrubs which have been shown to have medicinal properties and also are used as a culinary herb, preservative and flavoring agents. In this study methanol extracts from the leaves of Ocimum species (O. sanctum purple, O. sanctum green, O. gratissimum, O. basilicum and Camphor basil) were investigated for their phytochemical constituent and antioxidant activity. Also, six extracts (Ethanol, Methanol, Propanol, Chloroform, Petroleum Ether and Iso- amyl alcohol) were assayed to test their ability to inhibit the clinically isolated Enterobacteria (S. pneumoniae, Proteus sp., E. faecalis, S. typhi, S. aureus and B. subtilis). The Ocimum sp. were screened for the presence of phenolic content, glycosides, anthraquinones, terpe- noids, proteins, flavinoids, tannins, lignin and Saponins. The test results were positive for all Phytochemicals in methanolic extracts of Ocimum sp. The antioxidant activity was measured by reducing power assay, 1-1-diphenyl-2-picrylhydrazyl (DPPH) assay and Thiobarbi- turic acid (TBA) which showed positive. In the antimicrobial assay studies O. gratissimum and O. basilicum showed maximum antibacteri- al activity compared to other species with maximum activity in isoamyl alcohol extract. The Present investigation suggests that the phyto- chemical content and its antioxidant properties can be further studied for its application in health and in food industries. Furthermore, these species can be used as a source of novel drugs for the treatment of infectious diseases caused by pathogenic microorganisms.

The diversity, antimicrobial and anticancer activity of endophytic fungi associated with the medicinal plant Stryphnodendron adstringens (Mart.) Coville (Fabaceae) from the Brazilian savannah

The diversity and biological activities of the endophytic fungi associated with the Brazilian medicinal plant Stryphnodendron adstringens were studied. A total of 320 fungal isolates were obtained, and 66 phylotypes comprising 25 genera were identified. The fungal community of S. adstringens displayed high richness, diversity and low dominance indices. The most abundant phylotypes were closely related to Diaporthe phaseolorum, Guignardia camelliae, and Preussia pseudominima. Sixteen fungal extracts displayed biological activities when screened against bacteria, fungi, cancer cell lines, and amastigote forms of Leishmania amazonensis. The extract of phylotype Nigrospora cf. oryzae exhibited a selective antifungal activity and inhibited the growth of Candida albicans and Cladosporium sphaerospermum. The extracts of Diaporthe cf. phaseolorum and Xylaria sp. phylotypes displayed anticancer activities. Our results indicate that the endophytes associate with this medicinal plant may be a source for novel drugs.

Vibrational spectroscopy and electrophoresis as a “golden means” in monitoring of polysaccharides in medical plant and gels

In recent years, some bioactive polysaccharides isolated from natural sources have attracted much attention in the field of biochemistry and pharmacology. Of them, polysaccharides or their glycoconjugates were shown to exhibit multiple biological activities including anticarcinogenic, anticoagulant, immunostimulating, antioxidant, etc. Pharmacotherapy using plant-derived substances can be currently regarded as a very promising future alternative to conventional therapy. The advanced biotechnologies available today enable chemical investigation of well-defined bioactive plant components as sources of novel drugs. The need for safer drugs without side effects has led to the use of natural ingredients with proven safety. Special interest is focused on plant polysaccharides. This article attempts to review the current structural and conformational characterization of some importantly bioactive monosaccharides isolated from following plant cell-wall: Symphytum officinale (comfrey), Thymus pulegioides (thyme), Trigonella foenum-graecum L. (fenugreek), Tussilago farfara L. (coltsfoot), Hyssopus officinalis (hyssop), Althaea officinalis L. (marshmallow) and Equisetum arvense L. (horsetail). The chemical structures of monosaccharides were analysed using FTIR and Raman spectroscopies as well as cellulose acetate membrane electrophoresis (CAE). The dried plant samples were gently hydrolysed with sulphuric acid. The presence of glucuronic acid, galacturonic acid, alginic acid, glucose, mannose and xylose in the hydrolysates of reference substances and non-defatted plant films was proved. The possibility of a taxonomic classification of plant cell walls based on infrared and Raman spectroscopies and the use of spectral fingerprinting for authentication and detection of adulteration of products rich in cell-wall materials are discussed. Individual bands were selected to monitor the sugar content in medical plant cell walls and to confirm the identity of the analysed plants.

Anthropometric measures and vagal indexes of heart rate variability in a population with a high prevalence of Chagas disease—differences according to obesity status

The diversity and biological activities of the endophytic fungi associated with the Brazilian medicinal plant Stryphnodendron adstringens were studied. A total of 320 fungal isolates were obtained, and 66 phylotypes comprising 25 genera were identified. The fungal community of S. adstringens displayed high richness, diversity and low dominance indices. The most abundant phylotypes were closely related to Diaporthe phaseolorum, Guignardia camelliae, and Preussia pseudominima. Sixteen fungal extracts displayed biological activities when screened against bacteria, fungi, cancer cell lines, and amastigote forms of Leishmania amazonensis. The extract of phylotype Nigrospora cf. oryzae exhibited a selective antifungal activity and inhibited the growth of Candida albicans and Cladosporium sphaerospermum. The extracts of Diaporthe cf. phaseolorum and Xylaria sp. phylotypes displayed anticancer activities. Our results indicate that the endophytes associate with this medicinal plant may be a source for novel drugs.

ChemInform Abstract: Plant Volatiles: Production, Function and Pharmacology

AbstractReview: 296 refs.

Plant volatiles: Production, function and pharmacology

Plant volatiles typically occur as a complex mixture of low-molecular weight lipophilic compounds derived from different biosynthetic pathways, and are seemingly produced as part of a defense strategy against biotic and abiotic stress, as well as contributing to various physiological functions of the producer organism. The biochemistry and molecular biology of plant volatiles is complex, and involves the interplay of several biochemical pathways and hundreds of genes. All plants are able to store and emit volatile organic compounds (VOCs), but the process shows remarkable genotypic variation and phenotypic plasticity. From a physiological standpoint, plant volatiles are involved in three critical processes, namely plant–plant interaction, the signaling between symbiotic organisms, and the attraction of pollinating insects. Their role in these ‘‘housekeeping’’ activities underlies agricultural applications that range from the search for sustainable methods for pest control to the production of flavors and fragrances. On the other hand, there is also growing evidence that VOCs are endowed with a range of biological activities in mammals, and that they represent a substantially under-exploited and still largely untapped source of novel drugs and drug leads. This review summarizes recent major developments in the study of biosynthesis, ecological functions and medicinal applications of plant VOCs.

Antibacterial activity of traditional medicinal plants used by Haudenosaunee peoples of New York State

BackgroundThe evolution and spread of antibiotic resistance, as well as the evolution of new strains of disease causing agents, is of great concern to the global health community. Our ability to effectively treat disease is dependent on the development of new pharmaceuticals, and one potential source of novel drugs is traditional medicine. This study explores the antibacterial properties of plants used in Haudenosaunee traditional medicine. We tested the hypothesis that extracts from Haudenosaunee medicinal plants used to treat symptoms often caused by bacterial infection would show antibacterial properties in laboratory assays, and that these extracts would be more effective against moderately virulent bacteria than less virulent bacteria.MethodsAfter identification and harvesting, a total of 57 different aqueous extractions were made from 15 plant species. Nine plant species were used in Haudenosaunee medicines and six plant species, of which three are native to the region and three are introduced, were not used in traditional medicine. Antibacterial activity against mostly avirulent (Escherichia coli, Streptococcus lactis) and moderately virulent (Salmonella typhimurium, Staphylococcus aureus) microbes was inferred through replicate disc diffusion assays; and observed and statistically predicted MIC values were determined through replicate serial dilution assays.ResultsAlthough there was not complete concordance between the traditional use of Haudenosaunee medicinal plants and antibacterial activity, our data support the hypothesis that the selection and use of these plants to treat disease was not random. In particular, four plant species exhibited antimicrobial properties as expected (Achillea millefolium, Ipomoea pandurata, Hieracium pilosella, and Solidago canadensis), with particularly strong effectiveness against S. typhimurium. In addition, extractions from two of the introduced species (Hesperis matronalis and Rosa multiflora) were effective against this pathogen.ConclusionsOur data suggest that further screening of plants used in traditional Haudenosaunee medicine is warranted, and we put forward several species for further investigation of activity against S. typhimurium (A. millefolium, H. matronalis, I. pandurata, H. pilosella, R. multiflora, S. canadensis).

Current approaches to exploit actinomycetes as a source of novel natural products

For decades, microbial natural products have been one of the major sources of novel drugs for pharmaceutical companies, and today all evidence suggests that novel molecules with potential therapeutic applications are still waiting to be discovered from these natural sources, especially from actinomycetes. Any appropriate exploitation of the chemical diversity of these microbial sources relies on proper understanding of their biological diversity and other related key factors that maximize the possibility of successful identification of novel molecules. Without doubt, the discovery of platensimycin has shown that microbial natural products can continue to deliver novel scaffolds if appropriate tools are put in place to reveal them in a cost-effective manner. Whereas today innovative technologies involving exploitation of uncultivated environmental diversity, together with chemical biology and insilico approaches, are seeing rapid development in natural products research, maximization of the chances of exploiting chemical diversity from microbial collections is still essential for novel drug discovery. This work provides an overview of the integrated approaches developed at the former Basic Research Center of Merck Sharp and Dohme in Spain to exploit the diversity and biosynthetic potential of actinomycetes, and includes some examples of those that were successfully applied to the discovery of novel antibiotics.

Bacterial Community Analyses of Two Red Sea Sponges

Red Sea sponges offer potential as sources of novel drugs and bioactive compounds. Sponges harbor diverse and abundant prokaryotic communities. The diversity of Egyptian sponge-associated bacterial communities has not yet been explored. Our study is the first culture-based and culture-independent investigation of the total bacterial assemblages associated with two Red Sea Demosponges, Hyrtios erectus and Amphimedon sp. Denaturing gradient gel electrophoresis fingerprint-based analysis revealed statistically different banding patterns of the bacterial communities of the studied sponges with H. erectus having the greater diversity. 16S rRNA clone libraries of both sponges revealed diverse and complex bacterial assemblages represented by ten phyla for H. erectus and five phyla for Amphimedon sp. The bacterial community associated with H. erectus was dominated by Deltaproteobacteria. Clones affiliated with Gammaproteobacteria were the major component of the clone library of Amphimedon sp. About a third of the 16S rRNA gene sequences in these communities were derived from bacteria that are novel at least at the species level. Although the overall bacterial communities were significantly different, some bacterial groups, including members of Alphaproteobacteria, Gammaproteobacteria, Acidobacteria, and Actinobacteria, were found in both sponge species. The culture-based component of this study targeted Actinobacteria and resulted in the isolation of 35 sponge-associated microbes. The current study lays the groundwork for future studies of the role of these diverse microbes in the ecology, evolution, and development of marine sponges. In addition, our work provides an excellent resource of several candidate bacteria for production of novel pharmaceutically important compounds.

Capnellene, a natural marine compound derived from soft coral, attenuates chronic constriction injury‐induced neuropathic pain in rats

Natural compounds obtained from marine organisms have received considerable attention as potential sources of novel drugs for treatment of human inflammatory diseases. Capnellene, isolated from the marine soft coral Capnella imbricate, 4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[]pentalene-2,3a-diol (GB9) exhibited anti-inflammatory actions on activated macrophages in vitro. Here we have assessed the anti-neuroinflammatory properties of GB9 and its acetylated derivative, acetic acid 3a-hydroxy-4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[]pentalen-2-yl ester (GB10). Effects of GB9 or GB10 on the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in interferon-gamma (IFN-gamma)-stimulated mouse microglial BV2 cells were measured by Western blot. The in vivo effects of these compounds were examined in the chronic constriction injury (CCI) rat model of neuropathic pain, measuring thermal hyperalgesia, and microglial activation and COX-2 protein in lumbar spinal cord, by immunohistochemistry. In BV2 cells, GB9 and GB10 inhibited the expression of iNOS and COX-2, stimulated by IFN-gamma. Intrathecal administration of GB9 and GB10 inhibited CCI-induced nociceptive sensitization and thermal hyperalgesia in a dose-dependent manner. Intraperitoneal injection of GB9 inhibited CCI-induced thermal hyperalgesia and also inhibited CCI-induced activation of microglial cells and up-regulation of COX-2 in the dorsal horn of the lumbar spinal cord ipsilateral to the injury. Taken together, these data indicate that the marine-derived capnellenes, GB9 and GB10, had anti-neuroinflammatory and anti-nociceptive properties in IFN-gamma-stimulated microglial cells and in neuropathic rats respectively. Therefore, capnellene may serve as a useful lead compound in the search for new therapeutic agents for treatment of neuroinflammatory diseases.

Monoamine oxidase inhibitory activities of indolylalkaloid toxins from the venom of the colonial spider Parawixia bistriata: Functional characterization of PwTX-I

Colonial spiders evolved a differential prey-capture behaviour in concert with their venom chemistry, which may be a source of novel drugs. Some highly active tetrahydro-β-carboline (THβC) toxins were recently isolated from the venom of the colonial spider Parawixia bistriata; the spiders use these toxins as part of their chemical arsenal to kill and/or paralyze preys. The major THβC compound isolated from this venom was identified as 6-hydroxytrypargine, also known as PwTX-I. Most natural compounds of animal origin occur in low abundance, and the natural abundance of PwTX-I is insufficient for complete functional characterization. Thus, PwTx-I was synthesized using a Pictet–Spengler condensation strategy, and the stereoisomers of the synthetic toxin were separated by chiral chromatography. The fraction of venom containing a mixture of three natural THβC toxins and enantiomers of PwTx-I were analyzed for inhibition of monoamine oxidase (MAO)-A and -B and for toxicity to insects. We reveal that the mixture of the natural THβC toxins, as well as the enantiomers of PwTx-I, were non-competitive inhibitors of MAO-A and MAO-B and caused potent paralysis of honeybees. The (−)-PwTX-I enantiomer is 2-fold more potent than the (+)-PwTX-I enantiomer in the assays performed.

Antimicrobial Compounds from Coleonema album (Rutaceae)

Coleonema album, a member of the South African fynbos biome, was evaluated for its antimicrobial activity associated with its secondary metabolites. Ethanol- and acetone-based extracts obtained from plants from two different geographical areas were analyzed. A bioassay-guided fractionation methodology was followed for rapid and effective screening for the presence of bioactive compounds. The TLC-bioautographic method, used to screen the plant extracts for antimicrobial activity and localization of the active compounds, indicated the presence of a number of inhibitory compounds with activity against the microorganisms (E. coli, B. subtilis, E. faecalis, P. aeruginosa, S. aureus, M. smegmatis, M. tuberculosis, C. albicans, C. cucumerinum) tested. Evaluation of the inhibitory strength of each extract by the serial microdilution assay indicated that the C. album extracts inhibited effectively all the microorganisms, with the minimum inhibitory concentrations in the low mg ml(-1) range. Identification and structural information of the bioactive components were obtained by a combination of preparative TLC and LC-MS. It revealed the presence of coumarin aglycones which were responsible for the observed antimicrobial activities. The results of this study indicate that C. album possesses strong antimicrobial activity against a wide range of microorganisms that warrants further investigation into the use of the extracts or their active constituents as a potential source for novel drugs.

Biodiversity: A continuing source of novel drug leads

Abstract Nature has been a source of medicinal agents for thousands of years and continues to be an abundant source of novel chemotypes and pharmacophores. With only 5 to 15 % of the approximately 250 000 species of higher plants systematically investigated, and the potential of the marine environment barely tapped, these areas will remain a rich source of novel bioactive compounds. Less than 1 % of bacterial and 5 % of fungal species are currently known, and the potential of novel microbial sources, particularly those found in extreme environments, seems unbounded. To these natural sources can be added the potential to investigate the rational design of novel structure types within certain classes of microbial metabolites through genetic engineering. It is apparent that Nature can provide the novel chemical scaffolds for elaboration by combinatorial approaches (chemical and biochemical), thus leading to agents that have been optimized on the basis of their pharmacological activities. The proven natural product drug discovery track record, coupled with the continuing threat to biodiversity through the destruction of terrestrial and marine ecosystems and the current low number of new chemical entities in pharmaceutical industry pipelines, provides a compelling argument in favor of expanded multidisciplinary and international collaboration in the exploration of Nature as a source of novel leads for the development of drugs and other valuable bioactive agents.

High-throughput docking as a source of novel drug leads

Receptor-based virtual screening has become a viable source of novel leads in the pharmaceutical industry. The rapidly growing availability of structural information across protein families, the accessibility to increased computational power at affordable cost, as well as an improved understanding on how to effectively apply virtual screening technologies has contributed to their emergence. Nonetheless, continued improvement in the accuracy of scoring functions and a greater understanding of protein mobility is critical to advance the technology further.