Norditerpenoid alkaloids of Delphinium denudatum as cholinesterase inhibitors.

Three new norditerpenoids alkaloids, 1ß-hydroxy,14ß-acetyl condelphine (1), jadwarine-A (2), jadwarine-B (3) along with two known alkaloids isotalatizidine hydrate (4) and dihydropentagynine (5) were isolated from medicinal plant Delphinium denudatum. The structures of natural products 1-5 were established on the basis of HR-EIMS, 1H and 13C NMR (1D & 2D) spectroscopic data as well as by comparison from literature data. The structures of compound 1 and 4 were also confirmed by single crystal X-ray diffraction studies. In-vitro AChE and BChE enzyme inhibitory activities of compounds 1-5 and molecular docking studies were performed to investigate the possible molecular inhibitory mechanism of the isolated natural products. Compound 2, 4 and 5 showed competitive inhibitory effects by inhibiting AChE and BChE, respectively, while 1 and 3 showed non-competitive inhibition. This work is the first report that provides a supporting evidence about the use of constituents of Delphinium denudatum in cerebral dementia and Alzheimer diseases.

Synthesis, monoamine oxidase inhibition activity and molecular docking studies of novel 4-hydroxy-N'-[benzylidene or 1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides.

Three series of 4-hydroxy-N'-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9-11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy-N'-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide (9i) with an IC50 value of 0.11 ± 0.005 µM, whereas, methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 ± 0.01 µM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.

Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent ß-glucuronidase inhibitors.

Thirty N-arylidenequinoline-3-carbohydrazides (1-30) have been synthesized and evaluated against ß-glucuronidase inhibitory potential. Twenty four analogs showed outstanding ß-glucuronidase activity having IC50 values ranging between 2.11±0.05 and 46.14±0.95 than standard d-saccharic acid 1,4 lactone (IC50=48.4±1.25µM). Six analogs showed good ß-glucuronidase activity having IC50 values ranging between 49.38±0.90 and 80.10±1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent ß-glucuronidase inhibitors for further investigation.

Crystal structure of (E)-N'-benzyl-idene-2-meth-oxy-benzohydrazide.

In the title benzoyl-hydrazide derivative, C15H14N2O2, the dihedral angle between the planes of the two phenyl rings is 12.56 (9)°. The azomethine double bond adopts an E configuration stabilized by an N-H⋯O hydrogen bond. In the crystal, the components are linked by C-H⋯O inter-actions to form chains along the b axis.

Synthesis of 4-methoxybenzoylhydrazones and evaluation of their antiglycation activity.

A series of 4-methoxybenzoylhydrazones 1-30 was synthesized and the structures of the synthetic derivatives elucidated by spectroscopic methods. The compounds showed a varying degree of antiglycation activity, with IC50 values ranging between 216.52 and 748.71 µM, when compared to a rutin standard (IC50=294.46±1.50 µM). Compounds 1 (IC50=216.52±4.2 µM), 3 (IC50=289.58±2.64 µM), 6 (IC50=227.75±0.53 µM), 7 (IC50=242.53±6.1) and 11 (IC50=287.79±1.59) all showed more activity that the standard, and these compounds have the potential to serve as possible leads for drugs to inhibit protein glycation in diabetic patients. A preliminary SAR study was performed.

Crystal structure of 2-{[1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl-oxy]carbon-yl}benzoic acid.

In the title compound, C15H15N3O6, the dihedral angle between the planes of the benzene and imidazole rings is 34.93 (10)°. An intra-molecular C-H⋯O hydrogen bond is observed. In the crystal, O-H⋯N hydrogen bonds link the mol-ecules into chains parallel to the c axis.

Chemical and pharmacognostical characterization of two Malaysian plants both known as Ajisamat

Ajisamat, an herb commonly used as an aphrodisiac in the Malaysian traditional medicine, corresponds to two different species from different families - Salacia macrophylla Blume, Celastraceae, and Prismatomeris glabra (Korth.) Valeton, Rubiaceae. Macromorphological inspection of the vegetative parts both plants reveals only a slight difference in the arrangement of the petioles. Microscopic investigation of the plants roots used as crude drugs revealed however distinctive anatomical features. Prismatic calcium oxalate crystals and banded paratracheal parenchyma are characteristics of S. macrophylla while P. glabra displays an abundance as crystals. Other features such as vessels diameters and arrangements are also of diagnostic importance. Some of these characters were also identified in the powder of thes e plant materials and proposed for diagnostic purpose. The values for extraction of ethanol and water as well as total ash, acid-insoluble ash, water-soluble ash and sulfated ash were determined for both plants. Phytochemical studies were carried out on hexane and chloroform extracts of S. macrophylla and methanolic extract of P. glabra. S. macrophylla was shown to contain highly oxidized pentacyclic triterpenes while P. glabra contains anthraquinones. The pharmacognostical and hytochemical information can be utilised as the identification tools for Salacia macrophylla and Prismatomeris glabra .

(E)-4-Meth-oxy-N'-(3,4,5-trihy-droxy-benzyl-idene)benzohydrazide methanol monosolvate.

The title compound, C(15)H(14)N(2)O(5)·CH(3)OH, displays an E conformation about the azomethine double bond [C=N = 1.277 (2) Å] and the benzene rings are inclined to one another by 18.28 (9)°. An intra-molecular O-H⋯O hydrogen bond occurs between the para-OH group and one of the meta-O atoms of the 3,4,5-trihy-droxy-benzyl-idene group. In the crystal, the components are linked into a three dimensional network by O-H⋯O, O-H⋯N and C-H⋯O hydrogen bonds.

Methyl (E)-3,5-dimeth-oxy-2-{[2-(4-meth-oxy-benzo-yl)hydrazin-1-yl-idene]meth-yl}benzoate.

In the title compound, C(19)H(20)N(2)O(6), the azomethine [C=N = 1.269 (2) Å] double bond adopts an E conformation and the dihedral angle between the planes of the benzene rings is 17.41 (11)°. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R(2) (2)(16) loops. The dimers are connected by C-H⋯O and C-H⋯N hydrogen bonds, forming sheets lying parallel to (100).

(E)-4-Meth-oxy-N'-[(pyridin-4-yl)methyl-idene]benzohydrazide monohydrate.

In the title compound, C(14)H(13)N(3)O(2)·H(2)O, the azomethine double bond adopts an E conformation and the N-N=C-C torsion angle is 178.37 (19)°. The dihedral angle between the benzene and pyridine rings is 5.58 (12)° and the C atom of the meth-oxy group is roughly coplanar with its attached ring [deviation = 0.157 (3) Å]. In the crystal, the components are linked by O-H⋯O, O-H⋯N, N-H⋯O and C-H⋯O hydrogen bonds, forming (001) sheets. The water O atom accepts one N-H⋯O and two C-H⋯O inter-actions from the adjacent organic mol-ecule.

(E)-N'-(3,4-Dimeth-oxy-benzyl-idene)-4-meth-oxy-benzohydrazide.

In the title compound, C(17)H(18)N(2)O(4), the azomethine double bond adopts an E conformation with an N-N-C-C torsion angle of -178.3 (3)°. The benzene rings are almost coplaner, with a dihedral angle of 2.98 (14)° between their mean planes. In the crystal, the molecules are linked by N-H⋯O hydrogen bonds, resulting in chains of mol-ecules lying parallel to the b axis. The structure is further consolidated by rather weak C-H⋯O hydrogen-bonding inter-actions, resulting in six-membered rings about inversion centers linked into chains arranged parallel to the b axis.

Frequency of severe mitral stenosis in young female patients having pure mitral stenosis secondary to rheumatic heart disease.

BACKGROUND: High morbidity and mortality due to Rheumatic heart disease (RHD) associated with females is mainly because of late diagnosis on one hand and socioeconomic reasons on the other hand. Poor referral to tertiary care centres leads to delayed diagnosis which results in complications. The objectives of this cross-sectional descriptive study was to assess the frequency of severe mitral stenosis in woman of child bearing age, having pure mitral stenosis (MS) secondary to rheumatic heart disease. METHODS: Two hundred and fifty women of child bearing age with RHD were enrolled in the study using consecutive non-probability sampling technique. Out of these 250 patients, cases of pure MS were selected. Patients with associated mitral regurgitation and aortic valve disease were excluded. After admission, assessment of mitral valve stenosis was done with 2D colour Doppler echocardiography. RESULTS: Out of 250 consecutive patients of rheumatic carditis, 110 (44%) patients had pure mitral valve stenosis, 85 (34%) had stenosis with mitral regurgitation and 55 (22%) patients had both mitral and aortic valve problem of varying severity. Among 110 patients with pure mitral valve stenosis, 48 (43.6%) had severe mitral valve stenosis. Severe mitral valve gradient (MVG) and high pulmonary artery pressure (PAP) was observed in 66 (60%) and 49 (44.5%) of the patients respectively. CONCLUSION: This high frequency can be linked to lack of early detection of the disease at primary level, poor management of throat infections and poor rheumatic fever prophylaxis at community level.

Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis.

BACKGROUND: Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2) isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->6)}-beta-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50) was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. RESULTS: Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 +/- 0.18 - 48.90 +/- 0.40 microM but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 +/- 1.04 and 9.32 +/- 0.082 muM respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. CONCLUSION: Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis.

Bioactive constituents from Boswellia papyrifera.

Phytochemical investigation of the stem bark extract of Boswellia papyrifera afforded two new stilbene glycosides, trans-4',5-dihydroxy-3-methoxystilbene-5-O-{alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->6)]-beta-D-glucopyranoside (1), trans-4',5-dihydroxy-3-methoxystilbene-5-O-[alpha-L-rhamnopyranosyl-(1-->6)]-beta-D-glucopyranoside (2), and a new triterpene, 3alpha-acetoxy-27-hydroxylup-20(29)-en-24-oic acid (3), along with five known compounds, 11-keto-beta-boswellic acid (4), beta-elemonic acid (7), 3alpha-acetoxy-11-keto-beta-boswellic acid (8), beta-boswellic acid (9), and beta-sitosterol (10). The stilbene glycosides exhibited significant inhibition of phosphodiesterase I and xanthine oxidase. The triterpenes (3-9) exhibited prolyl endopeptidase inhibitory activities.