Indole Acetic Acid Derivatives Research Articles

CHROMATOGRAPHIC AND PHYTOBIOLOGICAL ASSESSMENT OF SOME NATURAL BORON-CONTAINING COMPOUNDS

Boron (B) has many roles in the plant kingdom, being an essential element for fundamental metabolic pathways, with reference to carbohydrates, ribonucleic acid, phenolic compounds, indole acetic acid derivatives, respiration, as well as for the structure of cell wall and integrity of plasma membrane, cell division, differentiation, and elongation at the level of meristematic tissues, growth of the pollen tube, grain maturation. It has also been shown that the low amount of B can cause sterility during herbal reproductive stage.For identification and quantitative determination of some natural B-containing compounds (BCCs), such as boric acid, fructoboric acid and its derivatives (Ca–fructose–B complex and Zn–fructose–B complex), sodium tetraborate, high-performance thin-layer chromatography (HPTLC)–ultraviolet (UV) densitometry method was used, based on the following experimental conditions: stationary phase HPTLC silica gel G 60 F254 precoated glass plates, mobile phase 2-propanol–water 8:2 (v/v), derivatization with chlorogenic acid.The phytobiological assessment of natural BCCs was carried out using Triticum test. A slight stimulation of the mean radicular elongation of wheat-germinated caryopses, compared to the reference, was recorded for fructoboric acid and its derivatives at a concentration of 0.1% expressed in B.

Bioformulation of Bacillus proteolyticus MITWPUB1 and its biosurfactant to control the growth of phytopathogen Sclerotium rolfsii for the crop Brassica juncea var local, as a sustainable approach.

Bacillus proteolyticus MITWPUB1 is a potential producer of biosurfactants (BSs), and the organism is also found to be a producer of plant growth promoting traits, such as hydrogen cyanide and indole acetic acid (IAA), and a solubilizer of phosphate. The BSs were reportedly a blend of two classes, namely glycolipids and lipopeptides, as found by thin layer chromatography and Fourier-transform infrared spectroscopy analysis. Furthermore, semi-targeted metabolite profiling via liquid chromatography mass spectroscopy revealed the presence of phospholipids, lipopeptides, polyamines, IAA derivatives, and carotenoids. The BS showed dose-dependent antagonistic activity against Sclerotium rolfsii; scanning electron microscopy showed the effects of the BS on S. rolfsii in terms of mycelial deformations and reduced branching patterns. In vitro studies showed that the application of B. proteolyticus MITWPUB1 and its biosurfactant to seeds of Brassica juncea var local enhanced the seed germination rate. However, sawdust-carrier-based bioformulation with B. proteolyticus MITWPUB1 and its BS showed increased growth parameters for B. juncea var L. This study highlights a unique bioformulation combination that controls the growth of the phytopathogen S. rolfsii and enhances the plant growth of B. juncea var L. Bacillus proteolyticus MITWPUB1 was also shown for the first time to be a prominent BS producer with the ability to control the growth of the phytopathogen S. rolfsii.

Design, Synthesis, and Optimization of Indole Acetic Acid Derivatives as Potent and Selective CRTH2 Receptor Antagonists: Discovery of ACT-774312.

Herein we report the structure-activity relationship (SAR) studies and optimization of new highly potent and selective CRTH2 receptor antagonists as potential follow-ups of our previous reported clinical candidate setipiprant (ACT-129968) for the treatment of respiratory diseases. Structural modification of the amide part of setipiprant (ACT-129968) led to the identification of the tetrahydrocarbazole derivative (S)-B-1 (ACT-453859) ((S)-2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetic acid). This compound which displayed a substantial improvement in potency in the presence of plasma versus setipiprant (ACT-129968) has exhibited an excellent overall pharmacokinetic profile. Further lead optimization to overcome a safety issue as observed in non-clinical studies with (S)-B-1 (ACT-453859), led to the discovery of the 4-azaindole derivative (S)-72 (ACT-774312) ((S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid) which was selected as a potential follow-up of setipiprant (ACT-129968).

Chemical characterization of cytotoxic indole acetic acid derivative from mulberry fruit (Morus alba L.) against human cervical cancer

The fruit of the white mulberry tree (Morus alba L.) is a multiple fruit with a sweet flavor commonly consumed around the world. Chemical investigation of the fruits led to the isolation of two indole acetic acid derivatives (1 −2) including a new compound, which turned out to be an isolation artifact, 3S-(β-D-glucopyranosyloxy)-2,3-dihydro-2-oxo-1H-indole-3-acetic acid butyl ester (1), along with five known compounds (3 −7). Compounds 2 and 7 were newly identified from mulberry fruit. The new isolation artifact (1) exhibited cytotoxic effect on human cervical cancer Hela cells in a dose-dependent manner. Compound 1 activated caspase-8, caspase-9, and caspase-3, followed by cleavage of PARP, a substrate of caspase-3, in a dose-dependent manner. Simultaneous alterations in protein expression of mitochondrial factors Bax, BID and Bcl-2 were also observed. A comparison between compounds 1 and 2 led to a structure-activity relationship analysis of the cytotoxic effect. These results suggest that compound 1 could be beneficial in human cervical cancer treatment, and provide a theoretical basis for further application of compound 1.

Environmental Growth Conditions of Trichoderma spp. Affects Indole Acetic Acid Derivatives, Volatile Organic Compounds, and Plant Growth Promotion

Trichoderma species are soil-borne filamentous fungi widely utilized for their many plant health benefits, such as conferring improved growth, disease resistance and abiotic stress tolerance to their hosts. Many Trichoderma species are able to produce the auxin phytohormone indole-3-acetic acid (IAA), and its production has been suggested to promote root growth. Here we show that the production of IAA is strain dependent and diverse external stimuli are associated with its production. In in vitro assays, Arabidopsis primary root length was negatively affected by the interaction with some Trichoderma strains. In soil experiments, a continuum effect on plant growth was shown and this was also strain dependent. In plate assays, some strains of Trichoderma spp. inhibited the expression of the auxin reporter gene DR5 in Arabidopsis primary roots but not secondary roots. When Trichoderma spp. and A. thaliana were physically separated, enhancement of both shoot and root biomass, increased root production and chlorophyll content were observed, which strongly suggested that volatile production by the fungus influenced the parameters analyzed. Trichoderma strains T. virens Gv29.8, T. atroviride IMI206040, T. sp. “atroviride B” LU132, and T. asperellum LU1370 were demonstrated to promote plant growth through volatile production. However, contrasting differences were observed with LU1370 which had a negative effect on plant growth in soil but a positive effect in plate assays. Altogether our results suggest that the mechanisms and molecules involved in plant growth promotion by Trichoderma spp. are multivariable and are affected by the environmental conditions.

FORMULATION AND EVALUATION OF ETODOLAC NIOSOMES BY MODIFIED ETHER INJECTION TECHNIQUE

Objectives: Niosomes are non-ionic surfactant based multilamellar or unilamellar vesicles with aqueous solution of solute that is enclosed by a membrane. Etodolac is an indole acetic acid derivative with half-life of 4 to 7hrs. It is used for the treatment of Rheumatoid arthritis. Whenever used orally, it has many systemic side effects, so it is not preferred orally. The aim of present study was to develop niosomes of Etodolac to avoid all drawbacks associated with it like first pass metabolism and side effects. Methods: In present study four niosomes formulations of Etodolac were successfully developed by modified ether injection technique using different nonionic surfactant i.e. Span 20, Span 40, Tween 20, Tween 40 and cholesterol. Formulations were evaluated for different parameters like particle size, entrapment efficiency, in-vitro release, stability studies. Results: Niosomes formulations of batch N3 shows maximum mean particle diameter i.e. 2.46 µm. The entrapment efficiency of the niosomes was between 66.52-78.32%. The entrapment efficiency was found to be higher with the batch N4 (78.32%). The cumulative percent drug release after 10 hrs of the Etodolac niosomes in between 40.59-78.55%. 68.5% for N1, 50.49% for N2, 40.59 for N3 and 78.55 for N4. Accelerated stability studies for 12 weeks revealed that the Etodolac niosomes formulations of batch N4 were stable at up to 450C. Conclusion: Study concludes that Etodolac can be delivered by niosomes dosage form effectively and all limitations associated with it can be avoided. Peer Review History: Article received on-16 September, Revised 24 October, Accepted 30 October, Available online 15 November 2016 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 4.5/10 Average Peer review marks at publication stage: 7.5/10 Reviewer(s) detail: Dr. Barkat Ali Khan, Kampala International University , Uganda, barki.gold@gmail.com Prof. Dr. Kapil Kumar, Global Institute of Pharmaceutical Education and Research, Kashipur, US Nagar, Uttarakhand, India, kapil5november@gmail.com Similar Articles: INVESTIGATION OF PRONIOSOMES GEL AS A PROMISING CARRIER FOR TRANSDERMAL DELIVERY OF GLIMEPIRIDE

Molecular Modeling Study on Diazine Indole Acetic Acid Derivatives for CRTH2 Inhibitory Activity.

In the present work, molecular modeling studies have been reported on a series of diazine indole acetic acid derivatives to analyze the structure-activity relationship studies of CRTH2 using fragment (Topomer CoMFA and HQSAR) and field (CoMFA and CoMSIA) based QSAR methods. Twenty-six compounds were used as a training set to establish the model, and six compounds were used as a test set to validate the model. The generated models exhibited good statistical results such as correlation coefficient (r2) and the cross-validated correlation coefficient (q2). Topomer CoMFA analysis yielded the q2 of 0.610 and r2 of 0.981. HQSAR model generated using bond and connectivity as fragment distinction and 3-6 as fragment size has the q2 value of 0.707 and conventional r2 value of 0.892 with five components. CoMFA model was assessed by cross-validated q2 value of 0.543 and r2 value of 0.901 with steric and electrostatic fields. CoMSIA model generated using steric, hydrophobic and donor fields with q2 value of 0.550 and r2 value of 0.888 was found to be the optimal model among the various models generated. The contour maps were generated to analyze the important structural features that regulate their inhibitory potency. From the result of contour maps we have suggested the critical sites for chemical modification which will be useful in designing potent compounds with improved activity.

Indoleacetic acid derivatives from the seeds of Ziziphus jujuba var. spinosa

A pair of diastereoisomers, the N-glycosylated derivatives of dioxindole-3-hydroxy-3-acetic acid 1–2, and their conjugates with flavonoids 3–8, was isolated from the seeds of Ziziphus jujuba var. spinosa. Their structures were elucidated by NMR spectroscopic analyses, and the absolute configurations were determined by circular dichroism method. Compounds 3–10 were evaluated for the antioxidant capacity, using the radical absorbance capacity (ORAC) assay.

Pharmacologic Profile of OC000459, a Potent, Selective, and Orally Active D Prostanoid Receptor 2 Antagonist That Inhibits Mast Cell-Dependent Activation of T Helper 2 Lymphocytes and Eosinophils

D prostanoid receptor 2 (DP₂) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D₂ (PGD₂). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [³H]PGD₂ from human recombinant DP₂ (K(i) = 0.013 μM), rat recombinant DP₂ (K(i) = 0.003 μM), and human native DP₂ (Th2 cell membranes; K(i) = 0.004 μM) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E₁₋₄ receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC₅₀ = 0.028 μM) of human Th2 lymphocytes and cytokine production (IC₅₀ = 0.019 μM) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD₂ in both isolated human leukocytes (pK(B) = 7.9) and human whole blood (pK(B) = 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD₂ (DK-PGD₂) in this species (ED₅₀ = 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD₂ in guinea pigs (ED₅₀ = 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP₂ antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.

Determination of the human cytochrome P450 isoforms involved in the metabolism of zolmitriptan

1. Zolmitriptan was extensively metabolized by freshly isolated human hepatocytes to a number of components including the three main metabolites observed in vivo (N-desmethyl-zolmitriptan, zolmitriptan N-oxide and the indole acetic acid derivative). In contrast, metabolism of zolmitriptan by human hepatic microsomes was extremely limited with only small amounts of the N-desmethyl and indole ethyl alcohol metabolites being produced. 2. Furafylline, a selective inhibitor of CYP1A2, almost completely abolished the hepatocellular metabolism of zolmitriptan and markedly inhibited formation of the N-desmethyl metabolite in microsomes. Chemical inhibitors, selective against other major human cytochrome P450 (CYP2C9, 2C19, 2D6 and 3A4), had no obvious effects. In addition, expressed human CYP1A2 was the only cytochrome P450 to form the N-desmethyl metabolite. 3. N-desmethyl-zolmitriptan was extensively metabolized by both human hepatocytes and microsomes. The indole acetic acid and ethyl alcohol derivatives were the major metabolites formed by hepatocytes, whereas only the indole ethyl alcohol derivative was produced by microsomes. Metabolism of N-desmethyl-zolmitriptan was not inhibited by cytochrome P450-selective chemical inhibitors nor was it observed following incubation with expressed human cytochrome P450. Clorgyline, a selective inhibitor of monoamine oxidase A (MAO-A), markedly inhibited the microsomal formation of the indole ethyl alcohol derivative. 4. Primary metabolism of zolmitriptan is dependent mainly on CYP1A2, whereas MAO-A is responsible for further metabolism of N-desmethyl-zolmitriptan, the active metabolite. Since the in vivo clearance of zolmitriptan is primarily dependent on metabolism, interactions with drugs that induce or inhibit CYP1A2 or MAO-A may be anticipated.

Characterization of the enzyme responsible for the metabolism of sumatriptan in human liver

Studies have been undertaken to investigate the enzymes responsible for the metabolism of [ 14C]sumatriptan in man. Oxidative deamination of sumatriptan to form the indole acetic acid derivative is the only phase 1 pathway evident in man and both cytochrome P450 (P450) and monoamine oxidase (MAO) are capable of catalysing this type of reaction. The metabolism of [ 14C]sumatriptan was therefore investigated in vitro in a preparation derived from human liver, which was shown, by the use of the probe substrates [ 14C]testosterone (P450), [ 3H]5HT (MAO-A) and [ 14C]benzylamine (MAO-B) to be a rich source of both enzyme systems. Incubation with clorgyline and deprenyl, probe inhibitors of MAO-A and MAO-B, respectively, showed that [ 14C]sumatriptan was metabolized by MAO-A; there was no evidence of P450 involvement in its metabolism. The data in this study therefore indicate that the enzyme MAO-A is the major enzyme responsible for the metabolism of sumatriptan in human liver.

The kinetics of 14C-GR43175 in rat and dog

GR43175 is a selective 5-HT 1-like receptor agonist which is effective in the acute treatment of migraine. Rats and dogs were dosed intravenously (iv) and orally (po) with 1 mg 14C-GR43175 base (as succinate salt)/kg bodyweight. GR43175 is rapidly absorbed after oral dosing. In dog, 95-100% of the dose is absorbed, but less (25-30%) is absorbed by the rat. The bioavailability is greater than 54% in dog, but lower in rat. Except for the CNS, drug-related material is widely distributed after iv dosing, but is mainly concentrated in the gastrointestinal tract and excretory organs after oral dosing. GR43175 is eliminated from plasma by a combination of renal and metabolic clearance. Some first-pass metabolism occurs in both species. In dog the major route of excretion is in urine (78-83% of the dose) after either route of administration. In rat, urine is also the major route of excretion (71%) after iv dosing. After oral dosing to the rat the major route of excretion is in the faeces (83%). GR43175 is extensively metabolized, after either route of administration, in both species. GR49336, the indole acetic acid derivative of GR43175, is the major metabolite in dog and a major metabolite in rat.

Nonsteroidal anti-inflammatory drugs and changing attitudes toward dysmenorrhea

Dysmenorrhea, which may be primary or secondary, is the occurrence of painful uterine cramps during menstruation. Until a decade ago, medical and social attitudes toward dysmenorrhea were shrouded with folklore, psychoanalytical profiles, or psychosomatic bases. In secondary dysmenorrhea, there is a visible pelvic lesion to account for the pain, whereas only a biochemical abnormality is responsible for primary dysmenorrhea. Recent advances in the biochemistry of prostaglandins and their role in the pathophysiology of primary dysmenorrhea and intrauterine device (IUD)-induced dysmenorrhea have now firmly established a rational basis for the disorder. In primary dysmenorrhea, menstrual prostaglandin release is significantly increased but can be readily suppressed to normal levels when nonsteroidal anti-inflammatory drugs (NSAIDs) capable of inhibiting cyclo-oxygenase are given during menstruation. Many clinical trials (controlled and uncontrolled) have demonstrated the efficacy of NSAIDs such as the fenamates, indole-acetic acid derivatives, and arylpropionic acid derivatives in relieving primary dysmenorrhea as well as IUD-induced dysmenorrhea that is also due to elevated prostaglandin levels. With a few of these NSAIDs, it has been shown that the relief of pain is associated with a significant decrease in menstrual fluid prostaglandin levels. Cumulative data of clinical trials indicate that with the effective NSAIDs, 80 percent of patients with significant primary dysmenorrhea can be adequately relieved. Ongoing studies suggest that in some women, endometrial leukotriene, but not PGF 2a production, is increased. With the official approval and availability of several effective NSAIDs for the specific treatment of primary dysmenorrhea in the United States, women who have primary dysmenorrhea have been greatly relieved and their productivity increased. Primary dysmenorrhea affects 50 percent of postpubescent women and absenteeism among the severe dysmenorrheics has been estimated to cause about 600 million lost working hours or 2 billion dollars annually. Thus, an effective, simple, and safe treatment of primary dysmenorrhea for two to three days during menstruation will not only have a positive economic impact but will also enhance the quality of life. The availability of effective dysmenorrhea therapy with NSAIDs has induced greater expectations of relief by the patient, as well as greater willingness to seek medical help, a more rational approach to patient management by physicians, changes in attitude toward women with primary dysmenorrhea, and the debunking of myths about dysmenorrhea that often have been perpetuated as fact. NSAIDs have undoubtedly revolutionized a painful disorder.

Synthesis of Indole Derivatives Attached to Polyethylene Oxides)

Abstract N-Benzyl 5-, 6-, and 7-bromoindolines were converted to the respective organosodium derivatives and used as initiators for the anionic polymerization of ethylene oxide. The resulting indoline derivatives attached to polyethylene oxide were dehydrogenated to the indole derivatives, which in turn were converted through suitable reactions to the tryptamine and indole acetic acid derivatives.

Synthesis of Poly-5-vinylindole Derivatives

Abstract 5-Vinyl-N-benzylindoline and 5-vinyl-N-benzylindole were synthesized starting from the corresponding 5-formyl derivative, by utilizing the Wittig or Wittig-Horner reactions. The monomers were polymerized by free-radical (AIBN) and anionic (BuLi) catalysts. Poly-5-vinyl-N-benzylindole was converted through suitable reactions to the tryptamine and indole acetic acid derivatives. Poly-5-vinyl-N-benzyl-tryptophane was synthesized by malonic ester synthesis by utilizing the condensation of poly-5-vinyl-N-benzylgramine and diethyl formamidomalonate.

Inhibition of Lettuce Seed Germination and Root Elongation by Derivatives of Auxin and Reversal by Derivatives of Cycocel

AbstractLettuce seed germination or lettuce root elongation after germination in water was inhibited by 5.7 × 10‐6M indoleacetic acid (IAA) and designated other IAA derivatives. These IAA‐inhibited growth responses were reversed by 10‐5 to 10‐6M Cycocel, (2‐chloroethyl) trimethylammonium chloride, which alone was without effect. Only those Cycocel analogs, which have previously been shown to be active as plant growth retardants, were effective in reversing IAA inhibition of germination or root elongation. These results are consistent with the concept that Cycocel at low concentrations acts as an auxin antagonist. However. Cycocel did not reverse the inhibitory effects from indole‐3‐propionic acid or indole‐3‐butyric acid.