Indole Acid Research Articles

Benzimidazole scaffolds as potential anticancer agents: Synthesis and Biological evaluation

Cancer continues to be one of the leading causes of mortality worldwide. Current anti‐cancer agents have a major limitation of drug resistance. Continued search for newer and safer anticancer drugs is critical and this led us to synthesize a small library of structurally unique benzimidazoles with anticancer potential. Various analogs of these compounds were derived from indole‐2‐carboxylic acid, fatty acids and alpha amino acids, providing a panel of diverse structures. Synthesized compounds were tested in three different cancer cell lines‐HepG2 (human hepatocellular carcinoma), HeLa (human cervical cancer), A549 (human lung carcinoma) and one transformed cell line HEK293 (human embryonic kidney). Many of the compounds tested induced cytotoxicity in a concentration‐dependent manner. Cell viability studies using MTT assay showed that indole and fatty acid based benzimidazoles were most potent followed by amino acid derivatives. Presence of protective functional groups decreased activity of the compounds. In order to investigate the mechanism of the cytotoxicity of the compounds, cleaved caspase 3 expression was measured and a fluorescence‐based apoptosis‐necrosis assay was performed. These results confirmed the presence of apoptosis process in cell death induced by the benzimidazole compounds. Furthermore, cell cycle alterations accompanied the cell death. In addition to anticancer activity, several of these compounds also showed promising antibacterial activity against S. aureus and S. epidermidis. Taken together, our findings demonstrate that the novel benzimidazole compounds could serve as potential leads for the further development of new anticancer agents.Support or Funding InformationFunding for this research was provided by College of Pharmacy and Health Sciences, St John's University, Queens, NYThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evidence for the Early Evolutionary Loss of the M20D Auxin Amidohydrolase Family from Mosses and Horizontal Gene Transfer from Soil Bacteria of Cryptic Hydrolase Orthologues to Physcomitrella patens

Inactive auxin conjugates are accumulated in plants and hydrolyzed to recover phytohormone action. A family of metallopeptidase orthologues has been conserved in Plantae to help regulate auxin homeostatic levels during growth and development. This hydrolase family was recently traced back to liverwort, the most ancient extant land plant lineage. Liverwort’s auxin hydrolase has little activity against auxin conjugate substrates and does not appear to actively regulate auxin. This finding, along with data that shows moss can synthesize auxin conjugates, led to examining another bryophyte lineage, Physcomitrella patens. We have identified and isolated three M20D hydrolase paralogues from moss. The isolated enzymes strongly recognize and cleave a variety of auxin conjugates, including those of indole butyric and indole propionic acids. These P. patens hydrolases not only appear to be “cryptic”, but they are likely to have derived from soil bacteria through Horizontal Gene Transfer. Additionally, support is presented that the plant-type M20D peptidase family may have been universally lost from mosses after divergence from the common ancestor with liverwort.

Tomato growth and resistance promotion by Enterobacter hormaechei subsp. steigerwaltii EB8D

Fusarium wilt is an economically important disease of tomato crop (Solanum lycopersicum L). Plant growth-promoting rhizobacteria (PGPR) represent an alternative to improve plant growth and yield as well as to act as agent of biocontrol. In this study, antagonistic effects of four selected isolates (EB8D, EB20J, EB24L and EB26M) were evaluated against Fusarium oxysporum f.sp. radicis lycopersici (FORL) as potential biocontrol agents in vitro and in vivo. After 30 days of culture, dry weight, length of stem and root were significantly (p ≤ .05) higher compared with the non-inoculated control. Compared with the control plate (inoculated only with pathogen), EB8D had showed efficient antagonism against FORL (48.88%). The different strains have been screened for siderophore production, solubilisation of mineral phosphates, synthesis of indolic acetic acid (IAA) to show the plant growth-promoting potential. The experimental groups were compared with a control group that did not receive any treatment by FORL, and EB8D was the best isolate in terms of growth promotion with an improvement of 73.85% of the stem length, 110.86% of the root length and 118.85% of the dry weight comparing with the non-treated controls. Compared with a control group treated by FORL, biocontrol activity has shown that EB8D strain improved the stem length with 111.85%, the root length with 118.85% and the dry weight with 452.38%. 16S rRNA analysis has confirmed that this strain belongs to the genus Enterobacter and has high similarity with Enterobacter hormaechei subsp. steigerwaltii (99.71%). EB8D has a significant strong protective potential against FORL and lead to better tomato growth and might have biotechnological potential for controlling fusarium wilt in tomato plants.

Ultra-performance liquid chromatography/mass spectrometry technology and high-throughput metabolomics for deciphering the preventive mechanism of mirabilite on colorectal cancer via the modulation of complex metabolic networks.

Colorectal cancer (CRC) is a highly virulent and malignant disease and always accompanied by metabolic disorders. Currently, there are no effective therapeutic drugs for the treatment of CRC. High-throughput metabolomics approaches have been used to unveil the metabolic pathways related to several diseases. In this study, ultra-performance liquid chromatography/mass spectrometry-based high-throughput metabolomics was used for deciphering the potential preventive mechanism of mirabilite on CRC via the modulation of the associated metabolic disorders; a total of 28 differential biomarkers, including indole acetaldehyde, 5-hydroxyindoleacetic acid, hypoxanthine, retinal, retinal ester, linoleic acid, stearic acid, 6-deoxocastasterone, 2-hydroxybutyric acid and LysoPC, were identified in the APCmin/+ mice. These differential biomarkers are involved in the tryptophan metabolism, glycerophospholipid metabolism and biosynthesis of unsaturated fatty acids. Note that these biomarkers and their disturbed metabolic pathways were also regulated by mirabilite. It has been found that the prevention of CRC by mirabilite is mainly associated with tryptophan metabolism; this study shows that high-throughput metabolomics can reveal the perturbed metabolic disorders targeted in the action mechanism of drug treatment.

Effect of Silver and Gold Nanoparticles on the Spectral and Luminescent Properties of a Merocyanine Dye

An increase in the concentration of silver nanoparticles (NP) initially causes an increase and then a decrease in the absorption and fluorescence intensities of a solution of tetramethinemerocyanine dye derived from indole and thiobarbituric acid. In the case of gold NP, the dye absorption remains unchanged, while fluorescence is reduced. The lifetime of the merocyanine fluorescent state does not change upon the addition of both types of nanoparticles. It is suggested that the observed effects are related to the action of plasmons in the metal nanoparticles on the electronic processes in the dye molecules.

N-Naphthoyl-substituted indole thio-barbituric acid analogs inhibit the helicase activity of the hepatitis C virus NS3

The hepatitis C virus (HCV) represents a substantial threat to human health worldwide. The virus expresses a dual-function protein, NS3 having both protease and RNA helicase activities that are essential for productive viral replication and sustained infections. While viral protease and polymerase inhibitors have shown great successes in treating chronic HCV infections, drugs that specifically target the helicase activity have not advanced. A robust and quantitative 96-well plate-based fluorescent DNA unwinding assay was used to screen a class of indole thio-barbituric acid (ITBA) analogs using the full-length, recombinant HCV NS3, and identified three naphthoyl-containing analogs that efficiently inhibited NS3 helicase activity in a dose-dependent manner, with observed IC50 values of 21–24 µM. Standard gel electrophoresis helicase assays using radiolabeled duplex DNA and RNA NS3 substrates confirmed the inhibition of NS3 unwinding activity. Subsequent anisotropy measurements demonstrated that the candidate compounds did not disrupt NS3 binding to nucleic acids. Additionally, the rate of ATP hydrolysis and the protease activity were also not affected by the inhibitors. Thus, these results indicate that the three ITBA analogs containing N-naphthoyl moieties are the foundation of a potential series of small molecules capable of inhibiting NS3 activity via a novel interaction with the helicase domain that prevents the productive unwinding of nucleic acid substrates, and may represent the basis for a new class of therapeutic agents with the potential to aid in the treatment and eradication of hepatitis C virus.

Enhanced photodesorption from near- and mid-infrared plasmonic nanocrystal thin films

The authors show that the desorption rate of two model molecules, indole and benzoic acid, from thin films of indium tin oxide nanocrystals supporting near- and mid-infrared (0.33–0.48 eV) localized surface plasmon resonances (LSPRs) is enhanced by as much as 60% upon illumination with broadband infrared light. The desorption rate increases linearly with light intensity. No increase in the desorption rate is detected for undoped In2O3 nanocrystal thin films or when photons resonant with the LSPR are blocked. The authors study the desorption rate enhancement as a function of illumination intensity, LSPR energy, and isotopic substitution. Importantly, the authors demonstrate the accelerated desorption via in-coupling of light to LSPRs with energies well within the mid-infrared. Their work opens the door to using these low energy photons as choreographers of chemical processes and sets the stage for future mechanistic studies.

Acetylcholinesterase inhibition and antimicrobial activity of hydroxyl amides synthesized from natural products derivatives.

Thirteen natural products derivatives of hydroxyl amide class, three described for the first time, were synthesized by reaction of three indole acids and 3,4,5-trimethoxybenzoic acid with six different amino alcohols in the presence of triphenylphosphine and N-bromosuccinimide. The derivatives were tested against the Gram (+) bacteria Staphylococcus aureus and Bacillus cereus, Gram (-) Pseudomonas aeruginosa and Escherichia coli, besides the yeast Candida albicans. One of the compounds (7) was selectively active against C. albicans (91.3 ± 0.49% inhibition) showing a great potential as a new drug lead, since it was more active than the positive control, miconazole (88.7 ± 2.41% inhibition). Regarding bacterial inhibition, compounds demonstrated mild activity, but inhibition of compounds 9, 10 and 13 towards E. coli is of interest since it is difficult to find drugs selectively active against Gram (-) bacteria. Most of the compounds were very active in the acetylcholinesterase inhibition assay. Compound 7 was again the most active (93.2 ± 4.47%), being more potent than the control galantamine (90.3 ± 0.45%). The most active gallic acid derivatives, compounds 3, 7 and 8 have in common, besides gallic acid skeleton, a (CH2)2OH group, which may be one of the structural requirements for AChE inhibition.

Diversity of plant growth promoting Rhizobacteria of Rhus Tripartitus in arid soil of Algeria (Ahaggar) and their physiological properties under abiotic stresses

Plant Growth Promoting Rhizobacteria (PGPR) associated with Ucria ( Rhus tripartitus) represents a good alternative for including this crop in revegetation programs in arid area. In this study, 137 bacterial strains were isolated in Tryptic Soy Agar medium (TSA) from six samples of ucria’s rhizospheric soil (Ahaggar, Algeria), based on colony characteristics, Gram © reaction, oxidase and catalase tests. To evaluate their PGP activities and their physiological characteristics under stress environment, ten tests were made. Sixty strains of 16 genera were selected for their PGPR abilities, which represent 43.79% to the total of rhizobacteria isolated. The maximum bacterial population were Bacillus (35%). 71.66% of isolates were able to solubilize the phosphate, 31.66% were able to produce Indole Acid Acetic (IAA), 58.33% were siderophore producers, 28,33% were able to produce Cyanhydric Acid (HCN) and 70% were able to grow without any source of nitrogen. Indeed, PGPR strains have shown tolerance and/or resistance to several experimental environmental conditions. As a conclusion, the PGPR strains of Ucria’s rhizosphere were shown a good potential for biofertilization and biocontrol of crops, and their tolerance to abiotic stresses is an interesting step to support their utilities.

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds 1–3 were scaled to supply material for preclinical studies, and indole 3 was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of 1 and 2 and 2.4 kg of 3. Multiple polymorphs of 3 were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified.

Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis.

It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone. To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular "waste" products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes. For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the Aβ precursor protein (APP) in the brain. We examined levels of Aβ in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. Aβ levels were also measured in the brain and in multiple tissues. Clearance of Aβ peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric Aβ40 and an increasing trend in Aβ42 in cervical and axillary lymph nodes of treated mice. 2- Statistically significant decreases in oligomeric Aβ40 and a decreasing trend Aβ42 in the brain. The data expands on our prior report that the lymphatic system participates in Aβ clearance from the brain. We propose that abnormalities in Aβ clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i.e., indole- 3-propionic acid) are known to inhibit Aβ aggregation although they do not reverse aggregated Aβ or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.

Catalytic and non-catalytic hydrothermal processing of Scenedesmus obliquus biomass for bio-crude production – A sustainable energy perspective

In the present study, hydrothermal liquefaction (HTL) of wet Scenedesmus obliquus biomass into bio-crude was carried out. Initially, the biochemical composition of S. obliquus biomass was examined, and it indicated high protein (56.1%) followed by carbohydrate (22.3%) and lipid (11.5%) contents. The ultimate analysis unveiled the presence of high carbon (48.1%) and oxygen (36.1%) in the biomass. This study had shed light on the selection of ideal reaction conditions such as temperature (200, 250, 300 °C), pressure (100, 200, 300 bar), and residence time (30, 60 min) for producing maximum bio-crude with/without catalyst aid. In the absence of the catalyst, a bio-crude yield of 35.7% was obtained at 300 °C temperature, 200 bar pressure, and 60 min residence time. On an interesting note, bio-crude yield was increased from 35.7 to 45.1% by adding homogeneous acid catalyst CH3COOH at 300 °C reaction temperature, which was higher than the other acid catalysts HCOOH (40%), H2SO4 (38%), HCl (39%), H3BO3 (37%), and the base catalysts NaOH (38%), KOH (37%), Na2CO3 (40%), K2CO3 (36%), Ca(OH)2 (37%). Elemental analyses of bio-crudes indicated a higher heating value of 35–40 MJ/kg, carbon-74%, nitrogen-5.86%, hydrogen-10.9%, sulfur <0.5 and oxygen content of 8.85%, which is comparable with petro-crude. Using CH3COOH as a catalyst in HTL led to reducing the oxygen content and simultaneously increased the higher heating value of bio-crude. In addition, GC-MS characterization of bio-crude indicated the presence of mono-aromatics, nitrogen heterocycles, phenols, indole and fatty acids. Thus, based on the yield and characteristics, the bio-crude produced from S. obliquus biomass could be used in petroleum refinery for fuel production.

Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5'-Adenosine Monophosphate-Activated Protein Kinase (AMPK).

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.

Divergent Oxidative Couplings between Indoles and 2,3-Dihydroxybenzoic Acid Derivatives for the Biomimetic Synthesis of Voacalgine A and Bipleiophylline

The present feature article details our endeavors towards the synthesis of the highly intricate bisindole alkaloid bipleiophylline and its biosynthetic precursor voacalgine A: from the development of a divergent oxidative coupling between indole and dihydroxybenzoic acids, to the exploration of the chemical space from natural products and culminating in the biomimetic assembly of voacalgine A and bipleiophylline.

Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.

Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism.

The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system–intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp–microbiome–immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.

Divergent Oxidative Couplings between Indoles and 2,3-Dihydroxybenzoic Acid Derivatives for the Biomimetic Synthesis of Voacalgine A and Bipleiophylline

The present feature article details our endeavors towards the synthesis of the highly intricate bisindole alkaloid bipleiophylline and its biosynthetic precursor voacalgine A: from the development of a divergent oxidative coupling between indole and dihydroxybenzoic acids, to the exploration of the chemical space from natural products and culminating in the biomimetic assembly of voacalgine A and bipleiophylline.

Necrotic enteritis challenge and high dietary sodium level affect odorant composition or emission from broilers.

Necrotic enteritis (NE) challenge and high dietary sodium (from sodium chloride) level on odor flux from broiler litter was investigated using 160 day-old Ross 308 male chicks randomly assigned to 4 dietary treatments with 4 replicates of 10 birds each. A 2 × 2 factorial arrangement of treatments was employed. Factors were: presence or absence of NE challenge and normal (1.6 g/kg) or high (4.0 g/kg) dietary sodium (Na) level. On d 20, odorants were collected from litter headspacewith a flux hood and measured using selected ion flow tube mass spectrometry (SIFT-MS). On d 33, while challenge did not lead to higher mortality, it reduced feed intake by 5.48% (P < 0.05) and body weight gain by 9.02% (P < 0.01) and worsened FCR by 5 points (P < 0.01), indicating subclinical necrotic enteritis occurred in challenged birds. Challenge increased (P < 0.01) litter moisture and litter headspace concentrations of dimethyl sulfide (P < 0.05), propyl mercaptan (P < 0.05), total butanols (P < 0.05), acetoin (P < 0.01), skatole (P = 0.05), butyric acid (P < 0.05), and methyl amine (P < 0.05) and tended to increase concentrations of ethyl mercaptan (P = 0.07), carbon disulfide (P = 0.09), indole (P = 0.10), and formic acid (P = 0.10) compared to the unchallenged group. The birds fed a high Na diet produced higher litter moisture (P < 0.01) and higher litter headspace concentration of sulfur compounds and phenol (P < 0.01) compared to those fed a normal Na diet. In the birds fed a high Na diet, challenge increased the litter flux of some additional odorants, which included 2,3-butanedione (P < 0.05), acetic acid (P < 0.01), propionic acid (P < 0.01), isobutyric acid (P < 0.01), isovaleric acid (P < 0.01), pentanoic acid (P < 0.05), 2-butanone (P < 0.05), and 3-methyl-1-butanol (P < 0.05). These findings suggest that both a high Na diet and sub-clinical NE increase the odor nuisance potential of broiler farms.

Integrated effect of plant growth-promoting rhizobacteria and phosphate-solubilizing microorganisms on growth of wheat (Triticum aestivum L.) under rainfed condition

BackgroundBiofertilizers are now considered to be the only alternative of chemical fertilizers which apart from their soaring cost are enhancing in pollution hazards of our environment. Increasing and extending the role of biofertilizers would reduce the need for chemical fertilizers and consequently decrease adverse environmental effects.ResultsAfter morphological and physiological characterization, 7 isolates out of 63 were selected as PGPR and seven as phosphate-solubilizing microbes (PSM). All seven PGPR exhibited indole acidic acid (IAA) production, whereas five isolates produced gibberellic acid (GA) ranging from 5.5 to 30.6 and 10.0 to 14.8 mg L−1, respectively, isolate WPR-51 have highest concentration of IAA and GA. Two isolates (WM-1 and WM-2) did not showed GA production in culture solution. Phosphate solubilizing index (SI) of seven isolates was recorded for 6 days in an incubation study. The P solubilization was also quantified through spectrophotometry and was found to range from 25 to 130.1 µg mL−1. These two isolates were further studied for their organic acid production (oxalic acid, citric acid and gluconic acids) through HPLC. The isolates PSM 202 showed higher acid production as compared to PSM-305. After biochemical screening, three PGPR (WRP-32, WRP-42 and WRP-51) and one PSM-202 were used in eight different combinations to test their effect on seed germination, seed vigor and root length in a 6-day Petri plates study. After laboratory study, a pot study was carried out, to verify the results of incubational experiment. Data were collected on root shoot length and root shoot biomass after 8 weeks of transplantation. Statistical analysis showed that among eight treatments, mixture or co-inoculation treatment (T8) (WPR-42 + WPR-51 + WPR-32 + PSM) ranked as first followed by treatment (T5) (WPR-51 + PSM) that significantly increased root shoot length and biomass as compared to un-inoculated treatment. Three PGPR isolates (WPR-42, WPR-51, WM-1) were also tested for their antifungal activity on seed germination of two wheat varieties and confirmed their antifungal activity against Rhizoctonia solani. The isolate WPR-51 and mixture of 3 isolates completely neutralized the harmful effects of Rhizoctonia solani as 100% of the seeds of both varieties germinated in these treatments.ConclusionThe integrated effect of co-inoculation treatment of selected PGPRs (WRP-32, WRP-42 and WRP-51) and PSM-202 were found better in promoting crop growth and controlling disease as compared to all others treatments.

Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells

A series of novel, heteroaryl carboxylic acid conjugates of the sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 human hematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03–0.30 μM and 0.04–0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0.05–0.40 μM and 0.04–0.61 μM, respectively, against 90% of the solid tumor cell lines in the NCI panel. Compound 7a was particularly effective against the sub-panel of breast cancer cell lines with GI50 values in the range <0.01–0.30 μM. Compounds 7j, 7a and its water soluble analog 7p also exhibited potent anticancer activity against rat 9L-SF gliosarcoma cells in culture. Compound 7j was the most potent compound in the series in the M9-ENL1 AML cell assay with a lethal dose concentration EC50 value of 720 nM, and exhibited the greatest cytotoxicity against a collection of primary AML stem cell specimens, which included a specimen that was unresponsive to PTL, affording EC50 values in the range 0.33–1.0 μM in three out of four specimens. The results from this study provide further evidence that analogs of the sesquiterpene MMB can be designed to afford molecules with significantly improved anticancer activity. Thus, both 7j and 7k are considered potential lead molecules in the search for new anticancer agents that can be used as treatments for both hematopoetic and solid tumors.