New cytotoxic spatane diterpenoids from marine alga Stoechospermum marginatum.

Three new spatane diterpenoids (1-3) were isolated from the brown alga Stoechospermum marginatum together with three known compounds (4-6). The structures of these compounds were determined by the detailed NMR spectroscopic and Mass spectrometric analyses. All the isolated compounds were screened for their cytotoxic potentials against a panel of four human cancer cell lines, which include DU145 (Prostate), B16F10 (Melanoma), MDA MB-231 (Breast), and HeLa (Cervical) along with a normal cell line (HEK). The screening results indicated that compounds 1, 4 and 5 displayed significant activities against B16F10 [IC50, 6.21 ± 0.14, 5.88 ± 0.21, 5.31 ± 0.24 µM] and MDA MB-231 [9.25 ± 0.61, 4.59 ± 0.14, 4.19 ± 0.13 µM] cell lines, respectively. In view of their significant activity, these compounds 1, 4 and 5 were further taken up for detailed fluorescence assays, scratch assay and flow cytometry analysis, which revealed that they diminished proliferation and arrested cell cycle in the S phase and G2/M phase, which induced cell death by apoptosis. Overall, based on their considerable results, these compounds could serve as lead molecules in the development of anticancer drug candidates.

Effects of Quinidine or Rifampin Co-administration on the Single-Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants.

This open-label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug-drug interaction between rilzabrutinib and quinidine (an inhibitor of P-glycoprotein [P-gp] and CYP2D6) or rifampin (an inducer of CYP3A and P-gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash-out period, after co-administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0-∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P-gp.

Synthesis of aminomethyl linked (+)-usnic acid derivatives via the Mannich reaction and evaluation of their biological activities.

(+)-Usnic acid (UA), a natural dibenzofuran derivative, abundantly produced by lichens and possess wide number of biomedical applications including antibacterial, anti-inflammatory, anti-oxidant and anticancer activities. In the present study, as series of usnic acid derivatives (3a-3i) were synthesised using Mannich reaction assessed for their antioxidant, α-glucosidase, and anticancer activities. The in vitro antioxidant activity showed that compound 3d displayed potent antioxidant activity by scavenging the activities of DPPH and ABTS+. The compounds 3d and 3e showed potent cytotoxic activity against HepG2 cancer cells by arresting the cell cycle at S phase and regulating the Bax/BcL2 expression and subsequently induce the apoptosis. Overall, the results clearly indicated that (+)-usnic acid derivatives bearing secondary amines are useful scaffolds for the development of drug candidates for treatment of oxidative stress mediated cancer and metabolic disorders.

Chemical profiling and simultaneous quantification of major bioactive constituents from Cocculus hirsutus by UPLC-QqQ-MS.

Cocculus hirsutus is a widely used herb in traditional systems of medicine for the treatment of various diseases. In the present study, five alkaloids (1-5), two flavonoids (6-7), one triterpenoid (8), and three steroids (9-10) were isolated from the roots of Cocculus hirsutus and further crude extract was analyzed by LC-Q-Tof-MS/MS in positive ionization mode leading to the identification of ten metabolites through comparison of exact molecular masses from their MS/MS spectra, mass fragmentation studies and with literature data. In addition, a method was developed and validated for the quantification of four bio-active compounds [Sinococuline (1), Magnoflorine (2), (E)-N-feruloyltyramine (3), and 20-Hydroxyecdysone (10)] using UPLC-QqQ-MS in multiple reaction monitoring (MRM) mode for the first time. The method has shown good linearity with correlation coefficients (r2) higher than 0.9916 for all four compounds. The intra- and inter-day precision were in the range of 0.3-6.1% and from 0.7% to 8.8%, respectively. The matrix effects of all the four analytes were found in the range of 94.7 ± 2.8-112.7 ± 3.7%. Overall, our study provides a reliable and rapid approach by hyphenated LC-MS/MS using high-resolution mass spectrometers for identification and quantification of bioactive constituents from the root extracts of Cocculus hirsutus.

Pharmacokinetics of recombinant factor VIII in adults with severe hemophilia A: fixed-sequence single-dose study of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa.

Background: Efanesoctocog alfa is a new class of factor (F) VIII replacement therapy designed to provide high sustained factor levels for longer by overcoming the von Willebrand factor half-life ceiling. Objectives: To assess the pharmacokinetics and safety of standard half-life (octocog alfa) and extended half-life (rurioctocog alfa pegol) FVIIIs and efanesoctocog alfa. Methods: This phase 1 study (NCT05042440; EudraCT 2021-000228-37) enrolled previously treated adult men with severe hemophilia A. Patients received sequential single 50-IU/kg doses of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa after appropriate washout periods between each dose. Results: Thirteen participants were enrolled. Geometric mean elimination half-life of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa was 11.0, 15.4, and 43.3 hours, respectively, and area under the FVIII activity-time curve was 1670, 2820, and 10,100 IU × h/dL, respectively. Efanesoctocog alfa maintained mean FVIII activity levels of >40 IU/dL for up to 4 days and at ∼10 IU/dL on day 7. Corresponding times for >40 IU/dL and >10 IU/dL were <1 and <2 days, respectively, for octocog alfa and 1 day and <3 days, respectively, for rurioctocog alfa pegol. No serious treatment-emergent adverse events were reported for efanesoctocog alfa, and no inhibitor development to FVIII was detected. Conclusion: Efanesoctocog alfa had 3- to 4-fold longer elimination half-life and 3- to 6-fold greater exposure (area under the FVIII activity-time curve, 6.03 and 3.57 folds) than octocog alfa and rurioctocog alfa pegol. Efanesoctocog alfa provided high sustained FVIII activity in the normal-to-near-normal range (>40 IU/dL) for up to 4 days after the dose and at ∼10 IU/dL on day 7.

Design, synthesis and biological evaluation of novel lipophilic 2, 5-disubstituted tetrazole analogues of muramyl dipeptide as NOD2 agonists.

A focused library of six new 2, 5-disubstituted tetrazole (2, 5-DST) analogues of N-acetylmuramyl-l-alanyl-d-isoglutamine (MDP) as potential immunomodulators were synthesized by the bioisosteric replacement of α-amide of d-isoglutamine with 5-substituted tetrazole (5-ST). Another parameter 'lipophilicity' was also considered to improve the pharmacological properties of MDP through the alkylation of 5-substituted tetrazole during synthesis. In total, six 2, 5-DST analogues of MDP were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, among the varied lengths of the alkyl chain in 2, 5-disubstituted tetrazole derivatives, the tetrazole analogues 12b bearing the -Butyl (C4) and 12c having -Octyl (C8) chain showed the best NOD2 stimulation potency equivalent with reference compound MDP. These analogues were evaluated for their adjuvanticity against dengue antigen and analogues 12b and 12c have elicited a potent humoral and cell mediated response.

Comprehensive Lichenometabolomic Exploration of Ramalina conduplicans Vain Using UPLC-Q-ToF-MS/MS: An Identification of Free Radical Scavenging and Anti-Hyperglycemic Constituents.

In this study, we propose ultra-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UPLC-QToF-MS/MS)-guided metabolite isolation as a choice analytical approach to the ongoing structure−activity investigations of chemical isolates from the edible lichen, Ramalina conduplicans Vain. This strategy led to the isolation and identification of a new depside (5) along with 13 known compounds (1−4, 6−14), most of which being newly described in this lichen species. The structures of the isolates were established by detailed analysis of their spectral data (IR, NMR, and Mass). The acetone extract was further analyzed by UPLC-Q-ToF-MS/MS in a negative ionization mode, which facilitated the identification and confirmation of 18 compounds based on their fragmentation patterns. The antioxidant capacities of the lichen acetone extract (AE) and isolates were measured by tracking DPPH and ABTS free radical scavenging activities. Most isolates displayed marked radical scavenging activities against ABTS while moderate activities were observed against DPPH radical scavenging. Except for atranol (14), oxidative DNA damage was limited by all the tested compounds, with a marked protection for the novel isolated compound (5), as previously noted for the acetone extract (p < 0.001). Furthermore, compound (4) and acetone extract (AE) have inhibited intestinal α-glucosidase enzyme significantly (p < 0.01). Although some phytochemical studies were already performed on this lichen, this study provided new insights into the isolation and identification of bioactive compounds, illustrating interest in future novel analytical techniques.

Facet-Dependent Bactericidal Activity of Ag3PO4 Nanostructures against Gram-Positive/Negative Bacteria.

Ag3PO4 nanostructures (APNs) containing silver (Ag metal; of the noble metal families) have the potential to exhibit enzyme-mimetic activity. A nanostructure shape, including its surface facets, can improve the bioactivity of enzyme mimicry, yet the molecular mechanisms remain unclear. Herein, we report facet-dependent peroxidase and oxidase-like activity of APNs with both antibacterial and biofilm degrading properties through the generation of reactive oxygen species. Cubic APNs had superior antibacterial effects than rhombic dodecahedral shapes when inhibiting Gram-positive and Gram-negative bacterial pathogen proliferation and biofilm degradation. A similar performance was observed for rhombic dodecahedral shapes, being greater than tetrahedral-shaped APNs. The extent of enzyme-mimetic activity is attributed to the facets {100} present in cubic APNs that led the peroxide radicals to inhibit the proliferation of bacteria and degrade biofilm. These facets were compared to rhombic dodecahedral APNs {110} and tetrahedral APNs {111}, respectively, to reveal a facet-dependent enhanced antibacterial activity, providing a plausible mechanism for shape-dependent APNs material enzyme-mimetic effects on bacteria. Thus, our research findings can provide a direction to optimize bactericidal materials using APNs in clinically relevant applications.

Bombax ceiba calyx displays antihyperglycemic activity via improving insulin secretion and sensitivity: Identification of bioactive phytometabolomes by UPLC-QTof-MS/MS.

Vegetables are considered good food for the management of hyperglycemia. Bombax ceiba L. (family: Bombacaceae) calyces are part of traditional vegetables. This study evaluated its usefulness on various parameters responsible for the development of hyperglycemia and conducted phytometabolomic analysis to identify phytochemicals responsible for the observed activities. It was found that the aqueous methanol extract of its calyces (B. ceiba calyx extract, BCE) reduced (12.4%) significantly (p < 0.05) the development of sucrose-induced postprandial hyperglycemic load in rats. In-vitro studies revealed that BCE improved glucose-stimulated insulin secretory activity in MIN6 cells plausibly by decreasing ADP/ATP ratio. BCE also augmented concentration-dependent (5 µg, 10 µg, and 20 µg) increase in glucose uptake in hyperglycemic L6 myotubes both by non-insulin-dependent manner (35%, 68%, and 132%, respectively) and insulin-dependent manner (42%, 59%, and 172%, respectively). The insulin-stimulated GLUT4 translocation was compromised (34%) significantly (p < 0.05) under hyperglycemic condition; however, it was improved by 23% and 72% (p < 0.001) when L6 myotubes were primed with 10 and 20 µg of BCE, respectively. Hyperglycemia aggravated reactive oxygen species (ROS) generation in L6 myotubes. The ROS generation was significantly (p < 0.001) reduced by priming myotubes with BCE before challenging myotubes to hyperglycemic environment, possibly by preserving cellular antioxidant enzymes catalase, glutathione peroxidase, and reduced glutathione levels. Phytometabolomic analysis disclosed a number of phytochemicals present in B. ceiba calyces known to display these activities. This is the first study reporting antihyperglycemic activity in B. ceiba calyces, its mechanisms of action, and phytometabolomic profile applying UPLC-QTof-MS/MS technique. PRACTICAL APPLICATION: B. ceiba calyces are part of traditional vegetables. Our study finds that B. ceiba calyces contain phytochemicals possessing antihyperglycemic, insulin secretory, insulin sensitization properties, and potentials for preserving hyperglycemia-induced vitiations in cellular antioxidant defense. These observations provide foundation for exploring further possibilities of B. ceiba calyces to become valuable dietary inclusion in the diet of people suffering from metabolic disorders.

A review on hydroxy anthraquinones from bacteria: crosstalk's of structures and biological activities.

Anthraquinones (AQ), unveiling large structural diversity, among polyketides demonstrate a wide range of applications. The hydroxy anthraquinones (HAQ), a group of anthraquinone derivatives, are secondary metabolites produced by bacteria and eukaryotes. Plant-based HAQ are well-studied unlike bacterial HAQ and applied as herbal medicine for centuries. Bacteria are known to synthesize a wide variety of structurally diversified HAQ through polyketide pathways using polyketide synthases (I, II & III) principally through polyketide synthase-II. The actinobacteria especially the genus Streptomyces and Micromonospora represent a rich source of HAQ, however novel HAQ are reported from the rare actinobacteria genera (Salinospora, Actinoplanes, Amycoloptosis, Verrucosispora, Xenorhabdus, and Photorhabdus. Though several reviews are available on AQ produced by plants and fungi, however none on bacterial AQ. The current review focused on sources of bacterial HAQ and their structural diversity and biological activities along with toxicity and side effects.

Efanesoctocog alfa for hemophilia A: results from a phase 1 repeat-dose study.

Efanesoctocog alfa (rFVIIIFc-VWF-XTEN; BIVV001) is a new class of factor VIII (FVIII) replacement that breaks the von Willebrand factor-imposed FVIII half-life ceiling. In a phase 1/2a study, single-dose efanesoctocog alfa was well tolerated, and no safety concerns were identified. We evaluated the safety, tolerability, and pharmacokinetics of repeat-dose efanesoctocog alfa in a phase 1 study in previously treated adults (≥150 exposure days) with severe hemophilia A. Participants received 4 once weekly doses of efanesoctocog alfa (cohort 1, 50 IU/kg; cohort 2, 65 IU/kg). All enrolled participants (cohort 1, n = 10; cohort 2, n = 14) completed the study. Inhibitor development to FVIII was not detected. After the last dose of efanesoctocog alfa, geometric mean (range) FVIII activity half-life, area under the activity-time curve, and steady-state maximum concentration for cohort 1 and cohort 2 were 41.3 (34.2-50.1) and 37.3 (28.9-43.8) hours, 8290 (5810-10 300) and 11 200 (7040-15 800) hours × IU/dL, and 131 (96-191) and 171 (118-211) IU/dL, respectively. There was minimal accumulation after 4 doses. Mean FVIII activity for cohort 1 and cohort 2, respectively, was 46% and 69% on day 3 postdose and 10% and 12% on day 7 postdose. Overall, 4 once-weekly doses of efanesoctocog alfa were well tolerated, no safety concerns were identified, and no bleeds were reported during the treatment period. Once-weekly efanesoctocog alfa provided high sustained FVIII activity within the normal to near-normal range for 3 to 4 days postdose and may improve protection against bleeds in patients with hemophilia A. The trial is study 2018-001535-51 in the EU Clinical Trials Register.

Population Pharmacokinetic Analysis of Recombinant Factor VIII Fc Fusion Protein in Subjects With Severe Hemophilia A: Expanded to Include Pediatric Subjects.

Recombinant factor VIII Fc fusion protein (rFVIIIFc) has been indicated for adults and children with hemophilia A. The objective of this article was to build a population pharmacokinetic (PK) model using adult and pediatric data sets and explore relevant dosing scenarios across all ages. The activity-time profiles of rFVIIIFc from 3 clinical studies (all trials registered at https://www.clinicaltrials.gov: NCT01027377, NCT01181128, and NCT01458106) were characterized, and covariates that determine variability of rFVIIIFc PK in children and adults were identified and implemented. Data sets were pooled to estimate population PK parameters. Simulations were conducted to generate activity-time profiles at steady state (SS). The proportion of subjects maintaining SS trough >1 and >3 IU/dL and time >10 IU/dL were estimated. The rFVIIIFc model was a two-compartment model that identified weight and von Willebrand factor as significant covariates. Model-predicted SS peaks and troughs of rFVIIIFc activity-time profiles confirmed the necessity of modifying dosing in pediatric subjects. The model also predicted that the average subject in the adult and adolescent group dosed with 40 IU/kg every 2 days maintained factor VIII activity >10 IU/dL for the entire duration. Children aged <6 years and aged 6 to <12 years receiving this dose maintained factor VIII activity of >10 IU/dL for nearly two-thirds and three-quarters of their time, respectively. In conclusion, these population PK analyses characterize activity-time profiles for rFVIIIFc among pediatric and adult subjects. The model was used for simulation of clinically relevant dosing scenarios, which can provide better protection and better clinical outcomes.

Phytometabolomic analysis of boiled rhizome of Nymphaea nouchali (Burm. f.) using UPLC-Q-TOF-MSE, LC-QqQ-MS & GC-MS and evaluation of antihyperglycemic and antioxidant activities.

Phytometabolomic analysis of Nymphaea nouchali (Burm. F.) boiled rhizome was carried out utilizing UPLC-Q-TOF-MSE, LC-QqQ-MS and GC-MS techniques and evaluated for antihyperglycemic and antioxidative stress potentials. Metabolomic analysis revealed presence of multiple antidiabetic and antioxidant compounds. Boiled rhizome powder exhibited potent antihyperglycemic activity against sugar-induced postprandial hyperglycemia in rats plausibly due to the presence of intestinal α-glucosidase inhibitory and augmenting cellular glucose uptake activities. It also prevented hyperglycemia-induced hemoglobin and insulin glycation. Rhizome displayed potent reducing power, effectively scavenged various reactive oxygen species. It displayed antioxidative stress potential in assuaging H2O2 induced erythrocyte hemolysis and antioxidant activity by inhibiting membrane lipid peroxidation. Boiled rhizome was also found to preserve the loss of cellular antioxidants under H2O2 induced oxidative stress and disturbances caused to mitochondrial membrane potential. This is the first research reporting boiled N. nouchali rhizome as an ideal food material to manage the cause of hyperglycemia and resultant oxidative stress.

BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A.

BACKGROUND: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).

UPLC-MSE Guided Isolation of New Antifeedant Limonoids from Fruits of Trichilia connaroides.

UPLC-MSE guided isolation of CHCl3 extract from the fruits of Trichilia connaroides yielded two new mexicanolide-type limonoids trichanolide F (1) and trichanolide G (2) along with a known compound carapanolide U (3). The structures of the limonoids were characterized by extensive spectroscopic analysis (MS, IR, 2D NMR). These limonoids (1-3) were evaluated for their antifeedancy against Spodoptera litura F. To further explore and draw the meaningful structure activity relationship studies, secophragmalin-type limonoids, namely, secotrichagmalin B, C (4, 5) and semisynthetic derivatives (5a-5l) were also screened for antifeedancy. The results revealed that trichanolide F (1) displayed highest antifeedant index (AFI) and caused larval mortality at 24 h. Derivative 5b caused larval toxicity, whereas 3, 5a, 5d, and 5g lead to pupal mortality and 2, 5f, 5k, and 5l caused adult deformities. Overall, the study provided new insights into the antifeedant potential of isolated and chemically modified limonoids from T. connaroides for the control of spodopteran pests.

Secophragmalin-Type Limonoids from Trichilia connaroides: Isolation, Semisynthesis, and Their Cytotoxic Activities.

Two new secophragmalin-type limonoids, secotrichagmalins B (1) and C (2) along with two known compounds, were isolated from the fruits of Trichilia connaroides. The structures of the new compounds were elucidated by analysis of spectroscopic (IR, MS, and 2D NMR) data and single crystal X-ray diffraction studies. In addition, semisynthetic derivatives (2a-2l) were efficiently synthesized and evaluated for their in vitro cytotoxicity along with the isolated limonoids against a panel of human cancer cell lines. The results indicated that new analogues 2a, 2d, and 2e showed cytotoxicity on the DU145 cell line with IC50 values of 3.6, 4.2, and 5.2 µM, respectively. Flow cytometric analysis revealed that these analogues arrested the cell cycle in the G0/G1 phase and markedly induced apoptosis.

Design, synthesis, molecular modelling, ADME prediction and anti-hyperglycemic evaluation of new pyrazole-triazolopyrimidine hybrids as potent α-glucosidase inhibitors.

The aim of the present study is to design and synthesis of new pyrazole-triazolopyrimidine hybrids as potent α-glucosidase inhibitors. The target compounds 4a-n were synthesized by one-pot multicomponent approach with good yields and were characterized by various spectroscopic techniques and finally by single crystal X-ray diffraction method (4j). All the newly-synthesized derivatives have been screened for their α-glucosidase enzyme inhibition activity and acarbose taken as a standard drug. Among all the tested compounds, 4h has displayed excellent α-glucosidase enzyme inhibition activity with IC50 value 12.45 µM to the standard drug acarbose (IC50: 12.68 µM). Similarly, the compounds 4f and 4l have exhibited potent activity with IC50 values 14.47 µM and 17.27 µM respectively. Structure-activity relationship (SAR) studies of all the title compounds were established. The mode of binding interactions between the α-glucosidase enzyme and the compounds were studied. The drug-likeness properties (Lipinski parameters and in silico ADME properties) have predicted for the target compounds. The α-glucosidase inhibition, molecular docking and drug-likeness properties of the compounds 4h, 4f and 4l were suggested that these are promising hits for anti-diabetic activity.

"Click" reaction based synthesis of nimbolide derivatives and study of their insect antifeedant activity against Spodoptera litura Larvae.

A series of Nimbolide-triazole conjugates were synthesized through copper(I)- catalyzed azide-alkyne "click" chemistry approach and these derivatives (2-4, 2a-2l) were characterized using modern spectroscopic techniques. Antifeedant activities of these derivatives were studied on Tobacco Caterpillar, Spodoptera litura (F.) using no-choice leaf disk bioassay. Interestingly, the synthesized derivatives were more effective in reducing feedancy by insect species when compared to the parent nimbolide. Among the tested compounds, 2a, 2c, and 2d showed potent antifeedancy with ED50 values of 0.49, 0.95 and 0.97mg/cm2 against S. litura. Several of the analogs were also toxic or caused developmental abnormalities following leaf disc assay.

Free radical scavenging, α-glucosidase inhibitory and anti-inflammatory constituents from Indian sedges, Cyperus scariosus R.Br and Cyperus rotundus L.

BACKGROUND: Cyperus scariosus R. Br and Cyperus rotundus L are widely used in ayurvedic preparation for the treatment of diabetes and other diseases. The early literature, so far, does not indicate the presence of any bioactive principle isolated from these plants. OBJECTIVE: To identify free radical scavenging, anti-diabetic and anti- inflammatory principles from these two species. MATERIALS AND METHODS: The bioassay guided fractionation and isolation of active constituents was done by chromatographic techniques. They also evaluated their anti-oxidant activity by DPPH and ABTS. The anti-diabetic activity was screened by α- glucosidase and α- amylase assays. Also, the further evaluation of in vitro anti-inflammatory activity using THP-1 monocytic cells and in vivo anti- inflammatory activity, was confirmed by carrageenan induced rat paw edema as model. RESULTS: The activity guided isolation led to isolation of twelve compounds Which are: Stigmasterol[1], ß- sitosterol[2], Lupeol[3], Gallic acid[4], Quercetin[5], ß- amyrin[6], Oleanolic acid[7], ß- amyrin acetate[8], 4- hydroxyl butyl cinnamate[9], 4- hydroxyl cinnamic acid[10], Caffeic acid,[11] and Kaempferol[12] respectively. Among the isolates, the compounds 4 and 5 displayed potent radical scavenging activity with an IC50 values of 0.43 and 0.067 ΅g/ml. The compounds 4, 5 and 10 showed significant anti-diabetic activities. while lupeol[3] showed potent IL-1 ß activity inhibition in THP-1 monocytic cells and also displayed significant (p<0.0025) in vivo anti-inflammatory activity. CONCLUSION: Inbrief, we isolated twelve compounds from both the species. Collectively, our results suggested that aromatic compounds showed good anti-oxidant and anti-diabetic activities. SUMMARY: The study investigates the free radical scavenging, α-glucosidase inhibitory and anti-inflammatory effects of constituents isolated from Indian sedges viz. C. scariosus and C. rotundus. The results indicated that phenolic compounds displayed potent fee radical scavenging activty and alpha-glucosidase inhibition activity. While terpene constituent, Lupeol[3] showed good IL-1ß activity inhibition in THP-1 monocytic cells and also displayed significant (p<0.0025) in vivo anti inflammatory activity in carrageenan induced rat paw edema. However, further studies are required to know the exact molecular mechanism. Abbreviations used: DPPH: 2,2- Diphenyl-1-1-picryl hydrazyl, ABTS: 2,2-Azinobis-3-ethylbenzo thiazoline-6-sulfonic acid, THP-1: Human leukaemia monocytic cell line, IL-1ß: Interleukin-1ß, IC50-Inhibitory concentration 50%.