High Selectivity Index Values Research Articles

Models for H3 receptor antagonist activity of sulfonylurea derivatives

The histamine H3 receptor has been perceived as an auspicious target for the treatment of various central and peripheral nervous system diseases. In present study, a wide variety of 60 2D and 3D molecular descriptors (MDs) were successfully utilized for the development of models for the prediction of antagonist activity of sulfonylurea derivatives for histamine H3 receptors. Models were developed through decision tree (DT), random forest (RF) and moving average analysis (MAA). Dragon software version 6.0.28 was employed for calculation of values of diverse MDs of each analogue involved in the data set. The DT classified and correctly predicted the input data with an impressive non-error rate of 94% in the training set and 82.5% during cross validation. RF correctly classified the analogues into active and inactive with a non-error rate of 79.3%. The MAA based models predicted the antagonist histamine H3 receptor activity with non-error rate up to 90%. Active ranges of the proposed MAA based models not only exhibited high potency but also showed improved safety as indicated by relatively high values of selectivity index. The statistical significance of the models was assessed through sensitivity, specificity, non-error rate, Matthew's correlation coefficient and intercorrelation analysis. Proposed models offer vast potential for providing lead structures for development of potent but safe H3 receptor antagonist sulfonylurea derivatives.

Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and NO production in LPS-activated J-774 cells

Here we report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring glycyrrhetinic acid bearing a 2-cyano-3-oxo-1-en moiety in the A-ring and double bonds and carbonyl groups in the C, D and E rings. Bioassays using murine macrophage-like and tumor cells show that compound 4, which differs from Soloxolone methyl by the absence of a 9(11)-double bond in the C-ring, displays anti-inflammatory and inhibitory activities with respect to tumor cells with a high selectivity index value.

Design, synthesis and biological evaluation of 3-benzyloxy-linked pyrimidinylphenylamine derivatives as potent HIV-1 NNRTIs

A novel series of 3-benzyloxy-linked pyrimidinylphenylamine derivatives (8a–8s) was designed, synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cell cultures. Most of the compounds inhibited wild-type (wt) HIV-1 replication in the lower micromolar concentration range (EC50=0.05–35μM) with high selectivity index (SI) values (ranged from 10 to >4870). In particular, 8h and 8g displayed excellent antiretroviral activity against wt HIV-1 with low cytotoxicity (EC50=0.07μM, CC50 >347μM, SI >4870; EC50=0.05μM, CC50=42μM, SI=777, respectively), comparable to that of the marked drug nevirapine (EC50=0.113μM, CC50 >15μM, SI >133). In order to confirm the binding target, 8h was selected to perform the anti-HIV-1 RT assay. Additionally, preliminary structure activity relationship (SAR) analysis and molecular docking studies of newly synthesized compounds were also discussed, as well as the predicted physicochemical properties.

Perovskatone A: a novel C23 terpenoid from Perovskia atriplicifolia

Perovskatone A (1), a novel C23 terpenoid with unique 6/7/7 carbon rings was isolated from Perovskia atriplicifolia, together with nine known compounds involving an rearranged diterpenoid demethylsalvicanol (2) and 7-methoxy-epirosmanol (3), hinokiol (4), isorosmanol (5), rosmanol (6), atuntzensin A (7), 7-methoxyrosmanol (8), oleanic acid (9), and ursolic acid (10). By detailed analyses of the MS, IR, and NMR data, the structure of perovskatone A (1) was definitely characterized. In vitro anti-HBV bioassay suggested perovskatone A (1) possessed superior inhibitory hepatitis B virus surface antigen (HBsAg), with a high selectivity index (SI) value of 7.56.

Antiviral activity of green tea catechins against feline calicivirus as a surrogate for norovirus

In this study, several medicinal plant extracts including spices, herb teas, and medical herbs were screened for antiviral activity against feline calicivirus (FCV), a surrogate of norovirus. Among them, a methanolic extract of green tea, Camellia sinensis, only exhibited a significant antiviral activity against FCV. The methanolic extract was further fractionated with several solvents such as methanol (MeOH), n-hexane, chloroform (CHCl3), ethyl acetate (EtOAc), n-butanol (n-BuOH), and water. EtOAc-soluble fraction exhibited the highest antiviral activity against FCV. Moreover, the analysis of the most active fraction using a HPLC led to the identification of 4 known catechins: (-)-epigallocatechin (EGC), (-)-epicatechin (EC), (-)-epigallocatechin gallate (EGCG), and (-)-epicatechin gallate (ECG). Among the catechins tested in this study, EGCG exhibited the most effective antiviral activity (EC50, 12 mg/mL) with relatively low cytotoxicity (CC50, 320 mg/ mL), resulting relatively high selectivity index value 26.67. To our knowledge, this is the first experimental verification showing antiviral activity of catechins from green tea against FCV.

Accumulation of mercury and other heavy metals in edible fishes of Cochin backwaters, Southwest India

Mercury, a global pollutant, has become a real threat to the developing countries like India and China, where high usage of mercury is reported. Mercury and other heavy metals deposited in to the aquatic system can cause health risk to the biota. The common edible fishes such as Mugil cephalus, Arius arius, Lutjanus ehrenbergii, Etroplus suratensis were collected from Cochin backwaters, Southwest India and analysed for mercury and other heavy metals (zinc, cadmium, lead and copper) in various body parts. Kidney and liver showed highest concentration of metals in most fishes. The omnivore and bottom feeder (E. suratensis) showed high concentration of mercury (14.71 mg/kg dry weight) and other metals (1.74 mg/g-total metal concentration). The average mercury concentration obtained in muscle was 1.6 mg/kg dry weight (0.352 mg/kg wet weight), which is higher than the prescribed limits (0.3 mg/kg wet weight). The concentration of other heavy metals in the muscles of fishes were found in a decreasing order Zn>Cu>Cd>Pb and are well below WHO permissible limits that were safe for human consumption. Metal selectivity index (MSI) obtained for all the metals except mercury showed that both carnivores and omnivores have almost same kind of affinity towards the metals especially Zn and Cd, irrespective of their feeding habit. The MSI values also indicate that the fishes have the potential to accumulate metals. High tissue selectivity index (TSI) values were reported for kidney, muscle and brain for all metals suggests that the metal concentration in these tissues can serve as an indication of metal polluted environment. Even if the daily intakes of Zn, Cd, Pb and Cu from these fishes are within the provisional maximum daily intake recommended by WHO/FAO, the quality is questionable due to the high hazard index obtained for mercury (>1). Fishes like E. suratensis being a favourite food of people in this region, the high consumption of it can lead to chronic disorders as this fish has high concentration of metals.

Discovery of novel anti-HIV active G-quadruplex-forming oligonucleotides

A series of d((5')TGGGAG(3')) sequences, 5'-conjugated with a variety of aromatic groups through phosphodiester linkages, were synthesized, showing CD spectra diagnostic of parallel-stranded, tetramolecular G-quadruplex structures. When tested for anti-HIV-1 and HIV-2 activity, potent inhibition of HIV-1 infection in CEM cell cultures was found, associated with high selectivity index values. Surface Plasmon Resonance assays revealed specific binding to HIV-1 gp120 and gp41.

Karavilagenin C derivatives as antimalarials

Karavilagenin C (1), a cucurbitane-type triterpenoid, previously isolated from the aerial parts of Momordica balsamina, was acylated with different alkanoyl, aroyl and cinnamoyl chlorides/anydrides, yielding ten new mono or diesters, karavoates F (7) and H-P (8-16). Furthermore, the new compound cucurbalsaminol C (17) was isolated from the same plant. Their structures were assigned by spectroscopic methods, including 2D NMR experiments. Compounds 1 and 17 and the acyl derivatives 8-16 along with other five esters (2-6, karavoates A-E), previously prepared from 1, were evaluated for their in vitro antimalarial activity against the chloroquine-sensitive (3D7) and the chloroquine-resistant (Dd2) strains of Plasmodium falciparum. Compound 1 exhibited a moderate activity and 17 was inactive. However, a remarkable antiplasmodial activity was observed for most of karavilagenin C alkanoyl and monoaroyl/cynamoyl derivatives. Karavoates B, D, E, I, and M were the most active, displaying IC(50) values similar to those found for chloroquine, particularly against the resistant strain (IC(50) <0.6μM). Structure-activity relationships (SAR) are discussed. Moreover, the preliminary toxicity toward human cells of compounds 1-17 was also evaluated in breast cancer cell line (MCF-7). Most of the esters showed no toxicity, displaying, in general, much higher selectivity index values than those obtained for the parent compound.

Models for prediction of anti- HIV-1 activity of 5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones using random forest, decision tree and moving average analysis

In the present study, an in silico approach using decision tree, random forest and moving average analysis has been applied to a data set comprising of 53 analogues of 5-alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3$H$)-one for development of models for prediction of anti-HIV-1 activity. A total of 46 2D and 3D molecular descriptors of diverse nature, have been used for decision tree and random forest analysis. The value of majority of these descriptors for each analogue in the dataset was computed using E-Dragon software (version 1.0). An in-house computer program was also employed to calculate additional topological descriptors which were not included in E-Dragon software. Random forest correctly classified the analogues into active and inactive with an accuracy of 85%. A decision tree was also employed for determining the importance of molecular descriptors. The decision tree learned the information from the input data with an accuracy of 98% and correctly predicted the cross-validated (10 fold) data with accuracy up to 77%. The best five descriptors identified by decision tree analysis were subsequently used to build suitable models using moving average analysis. The use of models based upon these non-correlating molecular descriptors resulted in the prediction of anti-HIV-1 activity with an overall accuracy of 83-96%. Moreover, active ranges of the proposed models not only revealed high potency but also exhibited improved safety as indicated by relatively high values of selectivity index. The statistical significance of models/ indices was assessed through intercorrelation analysis, sensitivity, specificity and Matthew's correlation coefficient. High predictability offer proposed models a vast potential for providing lead structures for development of potent but safe anti- HIV-1 agents.

Design, Synthesis, and SAR of Naphthyl‐Substituted Diarylpyrimidines as Non‐Nucleoside Inhibitors of HIV‐1 Reverse Transcriptase

A series of 38 2-naphthyl-substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild-type HIV-1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild-type HIV-1 with an EC50 value of 0.002 microM and against the double mutant strain with an EC50 value of 0.24 microM; the selectivity index (SI) against wild-type is >180 000, the highest SI value among DAPY analogues. The structure-activity relationship (SAR) of the newly synthesized DAPYs is presented herein.

Impact of Accessory Hepatic Veins on Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism

Adrenal vein sampling is the gold standard for identification of surgically curable primary aldosteronism, but its accuracy might be hindered by blood dilution from accessory vein blood. We prospectively investigated the presence of accessory veins draining into adrenal veins and their effect on the selectivity index (SI) in 74 consecutive patients undergoing adrenal vein sampling. On the right side, the venous anatomic pattern could be conclusively determined in 91.8% of the cases: we detected hepatic accessory veins in 12.1%, no accessory veins in 42.4%, and renal capsular veins in 45.5%. On the left side there was a phrenico-adrenal trunk in 89.4% and renal capsular accessory veins in 10.6% of the cases. On both sides, renal capsular and phrenic accessory veins did not affect the SI. At variance, on the right side, hepatic accessory veins were associated with SI values approximately 3-fold lower than that found when such accessory veins were absent (median: 3.10 [range: 0.80 to 84.2] versus median: 1.10 [range: 0.70 to 2.20]; P=0.01). However, superselective adrenal catheterization resulted into higher SI values (median: 23.88; range: 4.80 to 84.20) in these cases. Thus, hepatic accessory veins sharing egress into the inferior vena cava with the right adrenal vein occurred in approximately 12% of the patients and imply a low SI, likely because of adrenal blood dilution by hepatic blood carrying a low cortisol concentration. In the presence of this anatomic variation, superselective catheterization of the right adrenal vein should be undertaken to determine the lateralization of aldosterone secretion.

Indolizidine, antiinfective and antiparasitic compounds from Prosopis glandulosa var. glandulosa.

A new potent antiinfective and antiparasitic 2,3-dihydro-1H-indolizinium chloride (1) was isolated from Prosopis glandulosa var. glandulosa. Three additional new (2-4) and one known (5) indolizidines were also isolated, and the dihydrochloride salts of 1-3 (compounds 6, 7, and 8) were prepared. Structures were determined by 1D and 2D NMR and mass spectra. Compound 1 showed potent in vitro antifungal activity against Cryptococcus neoformans and Aspergillus fumigatus (IC(50) values = 0.4 and 3.0 microg/mL, respectively) and antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare (IC(50) values of 0.35 and 0.9 microg/mL, respectively). The remarkable in vitro fungicidal activity of 1-4 against C. neoformans (MFCs = 0.63-1.25 microg/mL) and 2, 3, and 5 against A. fumigatus (MFCs = 0.63-2.5 microg/mL) were similar to amphotericin B, but >2-4-fold more potent than 6-8. Prosopilosidine (1) showed potent in vivo activity at 0.0625 mg/kg/day/ip for 5 days in a murine model of cryptococcosis by eliminating approximately 76% of C. neoformans infection from brain tissue compared to approximately 83% with amphotericin B at 1.5 mg/kg/day. Compounds 1 and 4 exhibited potent activity and high selectivity index (SI) values against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum, with IC(50) values of 39 and 95 ng/mL and 42 and 120 ng/mL, respectively (chloroquine, IC(50) = 17 and 140 ng/mL). Prosopilosine (1) also showed in vivo antimalarial activity, with an ED(50) value of approximately 2 mg/kg/day/ip against Plasmodium berghei-infected mice after 3 days of treatment.

Comparative antiplasmodial, leishmanicidal and antitrypanosomal activities of several biflavonoids

The antiplasmodial, leishmanicidal and antitrypanosomal activities of eight natural biflavonoids were estimated in vitro on a chloroquine-resistant strain of Plasmodium falciparum, axenically grown Leishmania donovani amastigotes and Trypanosoma cruzi trypomastigotes and Trypanosoma brucei rhodesiense bloodstream forms. Lanaroflavone showed the highest antiplasmodial activity (IC(50) = 0.48 microM), isoginkgetin was the most active leishmanicidal compound (IC(50) = 1.9 microM), whereas ginkgetin (IC(50) = 11 microM) and isoginkgetin (IC(50) = 13 microM) showed the best antitrypanosomal activity in our assays. The cytotoxicity and the selectivity indices for the most active compounds were also estimated. Lanaroflavone exhibited a high selectivity index value (SI = 159), indicating selective antiplasmodial activity.

Diagnostic and prognostic significance of proteinuria selectivity index in glomerular diseases

The proteinuria selectivity index (SI) describes changes of the glomerular permeability for macromolecules. In the present study, we examine the implications of SI as a diagnostic (199 patients) and a prognostic (49 patients) marker in glomerular diseases. Using SI based on α 2-macroglobulin (α 2-M-SI) or on IgM (IgM-SI) we found that minimal change nephropathy could be discriminated by low SI values and crescentic necrotizing glomerulonephritis by high SI values compared to other diseases. SI based on IgG (IgG-SI) was less useful in determining specific diagnoses. During a follow-up of 46 months creatinine clearance (Cr cl) decreased 36% in a group of patients with high IgG-SI (>0.2) and 38% in a group of patients with high IgM-SI (>1.5 −3) compared to only 8% in patients with low IgG-SI (≤0.2) or low IgM-SI (≤1.5 −3). Furthermore, Cr cl decreased more than 30% in 12 (92%) out of thirteen patients with high baseline levels of both IgG-SI and IgM-SI compared to three out of thirteen patients with low baseline values of both the indexes. The decline rate of Cr cl correlated significantly to the SI levels but not to the degree of albuminuria. The findings of the study indicate that urinary excretion of high-molecular-weight proteins, and not of albumin, is a potential prognostic marker in proteinuric glomerulopathies and it may also serve as valuable diagnostic aid in these disorders.