Synthesis of alpha amylase inhibitors based on privileged indole scaffold

Twenty five derivatives of indole carbohydrazide (1–25) had been synthesized. These compounds were characterized using ¹H NMR and EI-MS, and further evaluated for their α-amylase inhibitory potential. The analogs (1–25) showed varying degree of α-amylase inhibitory potential.ranging between 9.28 and 599.0 µM when compared with standard acarbose having IC₅₀ value 8.78 ± 0.16 µM. Six analogs, 25 (IC₅₀ = 9.28 ± 0.153 µM), 22 (IC₅₀ = 9.79 ± 0.43 µM), 4 (IC₅₀ = 11.08 ± 0.357 µM), 1 (IC₅₀ = 12.65 ± 0.169 µM), 8 (IC₅₀ = 21.37 ± 0.07 µM) and 14 (IC₅₀ = 43.21 ± 0.14 µM) showed potent α-amylase inhibition as compared to the standard acarbose (IC₅₀ = 8.78 ± 0.16 µM). All other analogs displayed good to moderate inhibitory potential. Structure-activity relationship was established through the interaction of the active compounds with enzyme active site with the help of docking studies.     

Identification of new potent inhibitor of aldose reductase from Ocimum basilicum

Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3-hydroxypropyl)-3-methyl-8-β-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6′-hydroxyhex-3′-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC₅₀ value of 2.095 ± 0.77 µM compare to standard sorbinil (IC₅₀ = 3.14 ± 0.02 µM). Moreover, the compound (1) also showed multifolds higher activity (IC₅₀ = 0.783 ± 0.07 µM) against AKR1A1 as compared to standard valproic acid (IC₅₀ = 57.4 ± 0.89 µM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC₅₀ = 4.324 ± 1.25 µM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases.     

Syntheses of 4,6-dihydroxypyrimidine diones,their urease inhibition,in vitro,in silico,and kinetic studies

A library of 4,6-dihydroxypyrimidine diones (1–35) were synthesized and evaluated for their urease inhibitory activity. Structure-activity relationships, and mechanism of inhibition were also studied. All compounds were found to be active with IC₅₀ values between 22.6 ± 1.14–117.4 ± 0.73 µM, in comparison to standard, thiourea (IC₅₀ = 21.2 ± 1.3 µM). Kinetics studies on the most active compounds 2–7, 16, 17, 28, and 33 were performed to investigate their modes of inhibition, and dissociation constants K_i. Compounds 2, 3, 7, 16, 28, and 33 were found to be mixed-type of inhibitors with K_i values in the range of 7.91 ± 0.024–13.03 ± 0.013 µM, whereas, compounds 4–6, and 17 were found to be non-competitive inhibitors with K_i values in the range of 9.28 ± 0.019–13.05 ± 0.023 µM. In silico study was also performed, and a good correlation was observed between experimental and docking studies. This study is continuation of our previously reported urease inhibitory activity of pyrimidine diones, representing potential leads for further research as possible treatment of diseases caused by ureolytic bacteria.     

Carbohydrazones as new class of carbonic anhydrase inhibitors: Synthesis,kinetics, and ligand docking studies

Discovery and development of carbonic anhydrase inhibitors is crucial for their clinical use as antiepileptic, diurectic and antiglaucoma agents. Keeping this in mind, we have synthesized carbohydrazones 1–27 and evaluated them for their in vitro carbonic anhydrase inhibitory potential. Out of twenty-seven compounds, compounds 1 (IC₅₀ = 1.33 ± 0.01 µM), 2 (IC₅₀ = 1.85 ± 0.24 µM), 3 (IC₅₀ = 1.37 ± 0.06 µM), and 9 (IC₅₀ = 1.46 ± 0.12 µM) have showed carbonic anhydrase inhibition better than the standard drug zonisamide (IC₅₀ = 1.86 ± 0.03 µM). Moreover, compounds 4 (IC₅₀ = 2.32 ± 0.04 µM), 5 (IC₅₀ = 3.96 ± 0.35 µM), 7 (IC₅₀ = 2.33 ± 0.02 µM), and 8 (IC₅₀ = 2.67 ± 0.01 µM) showed good inhibitory activity. Cheminformatic analysis has shown that compounds 1 and 2 possess lead-like properties. In addition, kinetic and molecular docking studies were also performed to investigate the binding interaction between carbohydrazones and carbonic anhydrase enzyme. This study has identified a novel and potent class of carbonic anhydrase inhibitors with the potential to be investigated further.     

Biology-oriented drug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives,in vitro α-amylase inhibitory activity and in silico studies

A new library of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives (1 −2 3) were synthesized and characterized by EI-MS and ¹H NMR, and screened for their α-amylase inhibitory activity. Out of twenty-three derivatives, two molecules 19 (IC₅₀ = 0.38 ± 0.82 µM) and 23 (IC₅₀ = 1.66 ± 0.14 µM), showed excellent activity whereas the remaining compounds, except 10 and 17, showed good to moderate inhibition in the range of IC₅₀ = 1.77–2.98 µM when compared with the standard acarbose (IC₅₀ = 1.66 ± 0.1 µM). A plausible structure-activity relationship has also been presented. In addition, in silico studies was carried out in order to rationalize the binding interaction of compounds with the active site of enzyme.     

Synthesis of thiobarbituric acid derivatives: In vitro α-glucosidase inhibition and molecular docking studies

Synthesis, structure, and evaluation of in vitro α-glucosidase enzyme inhibition of a new class of diethylammonium salts of aryl substituted thiobarbituric acid is described. This protocol is straight, environmentally benign and efficient, involving Aldol-Michael addition reaction in one pot fashion. The 3D chemical structures of the synthesized compounds were assigned based on spectroscopic methods and X-ray single crystal diffraction analyses. All synthesized compounds 3a-3n were evaluated for their in vitro α-glucosidase enzyme inhibitory activity, whereas acarbose was used as the standard drug (IC₅₀ = 840 ± 1.73 µM). All tested compounds were found to possess varying degree of α-glucosidase enzyme inhibition activity with (IC₅₀ = 19.46 ± 1.84–415.8 ± 4.0 µM). Compound 3i (IC₅₀ = 19.4 ± 1.84 µM) exhibited the highest activity. To the best of knowledge this is the first report of the in vitro α-glucosidase enzyme inhibition by the diethylamonium salts of aryl substituted thiobarbituric acid. Furthermore, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites.     

Inhibitory effect of terpene nerolidol on the growth of Babesia parasites

Nerolidol is a sesquiterpene present in the essential oils of many plants, approved by the U.S. FDA as a food flavoring agent. Nerolidol interferes with the isoprenoid biosynthetic pathway in the apicoplast of P. falciparum. In the present study, the in vitro growth of four Babesia species was significantly (P < 0.05) inhibited in the presence of nerolidol (IC₅₀s values = 21 ± 1, 29.6 ± 3, 26.9 ± 2, and 23.1 ± 1 µM for B. bovis, B. bigemina, B. ovata, and B. caballi, respectively). Parasites from treated cultures failed to grow in the subsequent viability test at a concentration of 50 µM. Nerolidol significantly (P < 0.05) inhibited the growth of B. microti at the dosage of 10 and 100 mg/kg BW, while the inhibition was low compared with the high doses used. Therefore, nerolidol could not be used as a chemotherapeutic drug for babesiosis.     

Cytotoxic effects of stem bark extracts and pure compounds from Margaritaria discoidea on human ovarian cancer cell lines

Margaritaria discoidea (Baill.) G. L. Webster (Euphorbiaceae) is a well-known medicinal plant in Africa used for the treatment of various diseases. So far, no cytotoxic effects of plant extracts on cancer cell lines have been reported.Aim of the studyTo evaluate the cytotoxicity against human ovarian cancer cells of extracts of M. discoidea and characterize the major bioactive compounds.MethodsBoth organic and aqueous extracts of this plant were obtained by maceration. The sulforhodamine B cell proliferation assay was used for evaluation of their cytotoxic activities and the potential bioactive compounds were characterized by gas chromatography–mass spectrometry.ResultsThe organic extract of M. discoidea showed stronger cytotoxicity than the aqueous extract with IC₅₀ values of 14.4 ± 3.0, 14.2 ± 1.2 and 34.7 ± 0.5 µg/ml on OVCAR-8, A2780 and cisplatin-resistant A2780cis ovarian cancer cells, respectively. The organic extract was further subjected to bioassay-guided fractionation by partitioning with n-hexane, ethyl acetate, and n-butanol in water. The ethyl acetate fraction was the most potent on the three ovarian cancer cell lines. A GC–MS analysis of trimethylsilyl derivatives of this fraction indicated the presence of phenolic compounds such as gallic acid and the alkaloid securinine. The IC₅₀ values of these two compounds were determined to be in the range of 3–16 µM, which indicated that they could contribute to the cytotoxic activity of the extract of M. discoidea.ConclusionsThis study has evaluated the cytotoxicity of stem bark extracts of M. discoidea against ovarian cancer cells and provided a basis of further development of this plant for the treatment of ovarian cancer.     

Kinetic and thermodynamic analysis of the inhibitory effects of maltose,glucose, and related carbohydrates on wheat β-amylase

Inhibition of wheat β-amylase (WBA) by glucose and maltose was studied by kinetics and thermodynamics. The inhibitory effects of fructose, difructose, sucrose, trehalose, cellobiose, acarbose, and 1-deoxynojirimycin on WBA were also evaluated. The half maximal inhibitory concentrations (IC₅₀) of acarbose, maltose and glucose were 0.06 ± 0.01 M, 0.22 ± 0.09 M, and 1.41 ± 0.17 M, respectively. The inhibitor constant (K_i) and the thermodynamic parameters such as changes in Gibbs energy (ΔG), enthalpy (ΔH), and entropy (ΔS) of the dissociation reactions of the WBA-glucose and WBA-maltose complexes were temperature and pH-dependent. The dissociation reactions were endothermic and enthalpy-driven. Both glucose and maltose behaved as competitive inhibitors at pH 3.0 and 5.4 at a temperature of 25 °C with respective K_i values of 0.33 ± 0.02 M and 0.12 ± 0.03 M. In contrast, both sugars exhibited uncompetitive inhibition at pH 9 at a temperature of 25 °C with K_i values of 0.21 ± 0.03 M for glucose and 0.11 ± 0.04 M for maltose. The pH-dependence of the inhibition type and K_i values indicate that the ionizing groups of WBA influence drastically the interaction with these carbohydrates. This evidence enables us to consider temperature and pH in the WBA-catalyzed hydrolysis to manipulate the inhibition by end-product, maltose, and even by glucose.     

An investigative study of antitumor properties of a novel thiazolo[4,5-d]pyrimidine small molecule revealing superior antitumor activity with CDK1 selectivity and potent pro-apoptotic properties

New thiazolo[4,5-d]pyrimidine analogues were synthesized and biologically assessed in-vitro for their antineoplastic activity. The growth inhibitory effects of these compounds were assessed through the National Cancer Institute-United States of America (NCI-USA) anticancer screening program. Compound 5 (7-Chloro-3-(2,4-dimethoxyphenyl)-5-methylthiazolo[4,5-d]pyrimidine-2(3H)-thione) was found to have a potent and broad-spectrum cytotoxic action against NCI panel with GI₅₀ (50% growth inhibition concentration) mean graph midpoint (MG-MID) = 2.88 µM. MTT assay was used to determine IC₅₀ values of the most potent agent against HCT-116 colorectal carcinoma and WI-38 human lung fibroblast cell lines; 5.33 µM ± 0.69 and 21.69 µM ± 1.04, respectively. Flow cytometric analysis revealed that compound 5 triggered apoptosis and G2/M cell cycle arrest. The ability of compound 5 to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyclin B complex was evaluated, and its IC₅₀ value was 97 nM ± 2.33. Moreover, according to the gene expression analysis, compound 5 up-regulated p53, BAX, cytochrome c, caspases-3,-8 and-9 besides down-regulated Bcl-2. In conclusion, compound 5 exerted a potent pro-apoptotic activity through the activation of the intrinsic apoptotic pathway and arrested the cell cycle at the G2/M phase.     

Synthesis and in vitro study of benzofuran hydrazone derivatives as novel alpha-amylase inhibitor

The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1–25), characterized through different spectroscopic techniques such as ¹HNMR and EI-MS. All screened analog shows good α-amylase inhibitory potentials with IC₅₀ value ranging between 1.078 ± 0.19 and 2.926 ± 0.05 µM when compared with acarbose having IC₅₀ = 0.62 ± 0.22 µM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC₅₀ values 1.644 ± 0.128, 1.078 ± 0.19, 1.245 ± 0.25, 1.843 ± 0.19, 1.350 ± 0.24, 1.629 ± 0.015, 1.353 ± 0.232, 1.359 ± 0.119 and 1.488 ± 0.07 µM when compare with standard drug acarbose. All other analogs showed good to moderate α-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies.     

Temperature and sex dependent effects on cardiac mitochondrial metabolism in Atlantic cod (Gadus morhua L.)

To test the hypothesis that impaired mitochondrial respiration limits cardiac performance at warm temperatures, and examine if any effect(s) are sex-related, the consequences of high temperature on cardiac mitochondrial oxidative function were examined in 10 °C acclimated, sexually immature, male and female Atlantic cod. Active (State 3) and uncoupled (States 2 and 4) respiration were measured in isolated ventricular mitochondria at 10, 16, 20, and 24 °C using saturating concentrations of malate and pyruvate, but at a submaximal (physiological) level of ADP (200 µM). In addition, citrate synthase (CS) activity was measured at these temperatures, and mitochondrial respiration and the efficiency of oxidative phosphorylation (P:O ratio) were determined at [ADP] ranging from 25–200 µM at 10 and 20 °C. Cardiac morphometrics and mitochondrial respiration at 10 °C, and the thermal sensitivity of CS activity (Q₁₀=1.51), were all similar between the sexes. State 3 respiration at 200 µM ADP increased gradually in mitochondria from females between 10 and 24 °C (Q₁₀=1.48), but plateaued in males above 16 °C, and this resulted in lower values in males vs. females at 20 and 24 °C. At 10 °C, State 4 was ~10% of State 3 values in both sexes [i.e. a respiratory control ratio (RCR) of ~10] and P:O ratios were approximately 1.5. Between 20 and 24 °C, State 4 increased more than State 3 (by ~70 vs. 14%, respectively), and this decreased RCR to ~7.5. The P:O ratio was not affected by temperature at 200 μM ADP. However, (1) the sensitivity of State 3 respiration to increasing [ADP] (from 25 to 200 μM) was reduced at 20 vs. 10 °C in both sexes (K_m values 105±7 vs. 68±10 μM, respectively); and (2) mitochondria from females had lower P:O values at 25 vs. 100 μM ADP at 20 °C, whereas males showed a similar effect at 10 °C but a much more pronounced effect at 20 °C (P:O 1.05 at 25 μM ADP vs. 1.78 at 100 μM ADP). In summary, our results demonstrate several sex-related differences in ventricular mitochondrial function in Atlantic cod, and suggest that myocardial oxidative function and possibly phosphorylation efficiency may be limited at temperatures of 20 °C or above, particularly in males. These observations could partially explain why cardiac function in Atlantic cod plateaus just below this species׳ critical thermal maximum (~22 °C) and may contribute to yet unidentified sex differences in thermal tolerance and swimming performance.     

Phytosynthesis of silver nanoparticles from Jatropha integerrima Jacq. flower extract and their possible applications as antibacterial and antioxidant agent

Jatropha integerrima Jacq. flower extract was used for the synthesis of silver nanoparticles in the current study. Various spectroscopic analyses were used to characterize the synthesized nanoparticles (JIF-AgNPs). The antibacterial efficacy of JIF-AgNPs was studied by well diffusion and microdilution techniques. In addition, the impact of JIF-AgNPs on free radicals was evaluated. On the ultraviolet–visible spectrum, the nanoparticles exhibit the highest absorbance at 422 nm. Based on the Fourier transform infrared spectrum, phenols and amino acids were involved in capping the JIF-AgNPs. Crystalline sphere-shaped nanoparticles with an average size of 50.07 nm and zeta potential of ?19.0 mV were confirmed by X-ray diffraction, transmission electron microscopy, and dynamic light scattering analysis respectively. The JIF-AgNPs exhibit the highest and lowest growth inhibitory activity towards E. coli and B. subtilis. The minimal inhibitory concentration of JIF-AgNPs against E. coli, K. pneumoniae, S. aureus, and B. subtilis were 2.5, 5.0, 5.0, and 7.5 μg/mL, respectively. The JIF-AgNPs exhibited significant radical scavenging activities against DPPH (IC₅₀-32.5 ± 0.06 µg/mL), hydroxyl (IC₅₀-25 ± 0.09 µg/mL), Superoxide (IC₅₀-42.5 ± 0.13 µg/mL), and ABTs (IC₅₀-33.5 ± 0.15 µg/mL). Thus, synthesized nanoparticles were a good alternative to develop an antibacterial and antioxidant agent.     

Removal of Zn(II) ions from aqueous solution using Moringa oleifera Lam. (horseradish tree) biomass

The removal of Zn(II) ions from aqueous solution using pure and chemically pretreated biomass of Moringa oleifera was investigated at 30 ± 1 °C in this study. The experimental results explored that the maximum pH (pH_max) for efficient sorption of Zn(II) was 7 ± 0.1 at which evaluated biosorbent dosage and biosorbent particle size, were 0.5 g/L, <0.255 mm, respectively. The cellular Zn(II) concentration increased with the concentrations of Zn(II) in solution. Pretreatment of M. oleifera biomass affected the sorption process and the uptake capacity (mg/g) of biomass for Zn(II) uptake was in following order: NaOH (45.76) > H₂SO₄ (45.00) > CTAB (42.80) > Ca(OH)₂ (42.60) > Triton X-100 (42.06) > H₃PO₄ (41.22) > Al(OH)₃ (41.06) > SDS (40.41) > HCl (37.00) > non-treated biomass (36.07). There was significant increase in uptake capacity of M. oleifera biomass, which suggested that affinity between metal and sorbent can be increased after some sort of pretreatment. Both Langmuir and Freundlich isotherm model fitted well to data of Zn(II) biosorption as represented by high value of their correlation coefficient (i.e. R² ≈ 1). Kinetic studies revealed that Zn(II) uptake was fast with 90% or more of uptake occurring with in 40 min of contact time and the equilibrium was reached in 50 min of contact time. The sorption rates were better described by a second order expression than by a more commonly applied Lagergren equation. Finally it was concluded that pretreatment of M. oleifera biomass can achieve superior Zn(II) uptake capacity in comparison to non-pretreated biomass.     

Oleanolic acid (OA) as an antileishmanial agent: Biological evaluation and in silico mechanistic insights

Although a worldwide health problem, leishmaniasis is considered a highly neglected disease, lacking efficient and low toxic treatment. The efforts for new drug development are based on alternatives such as new uses for well-known drugs, in silico and synthetic studies and naturally derived compounds. Oleanolic acid (OA) is a pentacyclic triterpenoid widely distributed throughout the Plantae kingdom that displays several pharmacological activities. OA showed potent leishmancidal effects in different Leishmania species, both against promastigotes (IC_{50 L. braziliensis} 30.47 ± 6.35 μM; IC_{50 L. amazonensis} 40.46 ± 14.21 μM; IC_{50 L. infantum} 65.93 ± 15.12 μM) and amastigotes (IC_{50 L. braziliensis} 68.75 ± 16.55 μM; IC_{50 L. amazonensis} 38.45 ± 12.05 μM; IC_{50 L. infantum} 64.08 ± 23.52 μM), with low cytotoxicity against mouse peritoneal macrophages (CC₅₀ 235.80 ± 36.95 μM). Moreover, in silico studies performed to evaluate OA molecular properties and to elucidate the possible mechanism of action over the Leishmania enzyme sterol 14α-demethylase (CYP51) suggested that OA interacts efficiently with CYP51 and could inhibit the ergosterol synthesis pathway. Collectively, these data indicate that OA is a good candidate as leading compound for the development of a new leishmaniasis treatment.     

The silk cocoon of the silkworm,Bombyx mori: Macro structure and its influence on transmural diffusion of oxygen and water vapor

The cocoon of insect larvae is thought to help conserve water while affording mechanical protection. If the cocoon is a barrier to water loss, then it must also impose a barrier to inward oxygen diffusion. We tested this hypothesis in pupae of the silkworm, Bombyx mori. The rate of water loss and oxygen uptake (V?O₂) at 25 °C was measured in control pupae in their naturally spun cocoon and in exposed pupae experimentally removed from their cocoon. Additional measurements included the oxygen diffusion coefficient, DO₂, of the cocoon wall and dimensions and density of the cocoon fibers. Water loss (as % body mass loss) in both control and exposed pupae was ～ 1%^.day^? 1, and was not significantly different between populations. Similarly, V?O₂ was statistically identical in both control and exposed pupae, at 0.22 ± 0.01 and 0.21 ± 0.02 mL g^? 1 · h^? 1, respectively. The silk fiber diameter was significantly different in the outer fibers, 26 ± 1 µm, compared with 16 ± 1 µm for the inner fibers lining the cocoon. Inner fibers were also spun significantly more densely (20.8 ± 1.2 mm^? 1 transect) than outer fibers (8.3 ± 0.2). Mean DO₂ at 25 °C was 0.298 ± 0.002 cm² · s^? 1, approximately the same as unstirred air. These data indicate that the cocoon, while creating a tough barrier offering mechanical protection to the pupa, imposes no barrier to the diffusion of oxygen or water vapor.     

Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis,biological evaluation and molecular modeling studies

A series of new biphenyl bis-sulfonamide derivatives 2a–3p were synthesized in good to excellent yield (76–98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC₅₀ 0.04 ± 0.0001 μM for AChE) and (IC₅₀ 0.85 ± 0.0001 μM for BChE), the IC₅₀ values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 μM for AChE and 7.74 ± 0.07 to <400 μM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC₅₀ 2.27 ± 0.01 μM), whereas 3g exhibited the highest inhibition for BChE (IC₅₀ 7.74 ± 0.07 μM). Structure–activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.     

Gastro-intestinal handling of water and solutes in three species of elasmobranch fish,the white-spotted bamboo shark,Chiloscyllium plagiosum,little skate,Leucoraja erinacea and the clear nose skate Raja eglanteria

The present study reports aspects of GI tract physiology in the white-spotted bamboo shark, Chiloscyllium plagiosum, little skate, Leucoraja erinacea and the clear nose skate, Raja eglanteria. Plasma and stomach fluid osmolality and solute values were comparable between species, and stomach pH was low in all species (2.2 to 3.4) suggesting these elasmobranchs may maintain a consistently low stomach pH. Intestinal osmolality, pH and ion values were comparable between species, however, some differences in ion values were observed. In particular Ca²⁺ (19.67 ± 3.65 mM) and Mg²⁺ (43.99 ± 5.11 mM) were high in L. erinacea and Mg²⁺ was high (130.0 ± 39.8 mM) in C. palgiosum which may be an indication of drinking. Furthermore, intestinal fluid HCO₃^? values were low (8.19 ± 2.42 and 8.63 ± 1.48 mM) in both skates but very high in C. plagiosum (73.3 ± 16.3 mM) suggesting ingested seawater may be processed by species-specific mechanisms. Urea values from the intestine to the colon dropped precipitously in all species, with the greatest decrease seen in C. plagiosum (426.0 ± 8.1 to 0 mM). This led to the examination of the molecular expression of both a urea transporter and a Rhesus like ammonia transporter in the intestine, rectal gland and kidney in L. erinacea. Both these transporters were expressed in all tissues; however, expression levels of the Rhesus like ammonia transporter were orders of magnitude higher than the urea transporter in the same tissue. Intestinal flux rates of solutes in L. erinacea were, for the most part, in an inward direction with the notable exception of urea. Colon flux rates of solutes in L. erinacea were all in an outward direction, although absolute rates were considerably lower than the intestine, suggestive of a much tighter epithelia. Results are discussed in the context of the potential role of the GI tract in salt and water, and nitrogen, homeostasis in elasmobranchs.     

Synthesis,in vitro α-glucosidase inhibitory activity and molecular docking studies of new thiazole derivatives

Current study based on the synthesis of new thiazole derivatives via “one pot” multicomponent reaction, evaluation of their in vitro α-glucosidase inhibitory activities, and in silico studies. All synthetic compounds were fully characterized by ¹H NMR, ¹³C NMR and EIMS. CHN analysis was also performed. These newly synthesized compounds showed activities in the range of IC₅₀ = 9.06 ± 0.10–82.50 ± 1.70 μM as compared to standard acarbose (IC₅₀ = 38.25 ± 0.12 μM). It is worth mentioning that most of the compounds such as 1 (IC₅₀ = 23.60 ± 0.39 μM), 2 (IC₅₀ = 22.70 ± 0.60 μM), 3 (IC₅₀ = 22.40 ± 0.32 μM), 4 (IC₅₀ = 26.5 ± 0.40 μM), 6 (IC₅₀ = 34.60 ± 0.60 μM), 7 (IC₅₀ = 26.20 ± 0.43 μM), 8 (IC₅₀ = 14.06 ± 0.18 μM), 9 (IC₅₀ = 17.60 ± 0.28 μM), 10 (IC₅₀ = 27.16 ± 0.41 μM), 11 (IC₅₀ = 19.16 ± 0.19 μM), 12 (IC₅₀ = 9.06 ± 0.10 μM), 13 (IC₅₀ = 12.80 ± 0.21 μM), 14 (IC₅₀ = 11.94 ± 0.18 μM), 15 (IC₅₀ = 16.90 ± 0.20 μM), 16 (IC₅₀ = 12.60 ± 0.14 μM), 17 (IC₅₀ = 16.30 ± 0.29 μM), and 18 (IC₅₀ = 32.60 ± 0.61 μM) exhibited potent inhibitory potential. Molecular docking study was performed in order to understand the molecular interactions between the molecule and enzyme. Newly identified α-glucosidase inhibitors except few were found to be completely non-toxic.