1,3-di-4-piperidylpropane derivatives as potential acetyl cholinesterase antagonists: Molecular docking, synthesis, and biological evaluation.

Acetylcholine esterase (AChE) is a key biological target responsible for the management of cholinergic transmission, and its inhibitors are used for the therapy of Alzheimer's disease. In the present study, a small library of molecules with 1,3-di-4-piperidylpropane nucleus were docked on AChE. The selected compounds were synthesized and evaluated for their enzyme inhibition. P25 and P17 expressed significantly higher AChE inhibition than standards with IC50 values of 0.591µM and 0.625µM, respectively. Binding mode of derivatives in the active site of AChE revealed dual binding of molecules in peripheral anionic site (PAS) and catalytic anionic site (CAS) of enzyme cavity.

Gallic and vanillic acid suppress inflammation and promote myelination in an in vitro mouse model of neurodegeneration.

Neuroinflammation affects millions of people around the world as a result of injury or stress. Neuroinflammation represents almost all types of neurological diseases such as multiple sclerosis and Alzheimer's disease. Neurodegenerative diseases comprise demyelination and synaptic loss. The inflammatory response is further propagated by the activation of glial cells and modulation of constitutively expressed extracellular matrix proteins. The aim of the present study was to identify the anti-inflammatory effects of purified compounds gallic acid (GA, 1.0 µM) and vanillic acid (VA, 0.2 µM) on the lysolecithin (LPC, 0.003%)-induced model of inflammation. Hippocampal neurons were co-cultured with glial cells, and LPC was added to induce inflammation. Neurite outgrowth was measured by morphometry software. The level of myelination and demyelination was identified by immunostaining and sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blotting techniques using different antibodies. Whole-cell patch clamp recordings were used to observe the sustained repetitive firing pattern. The data showed that GA and VA significantly increased the neurite outgrowth after 48 h in culture. Both compounds significantly reduced the expression of cyclooxygenase-2, NFκB, tenascin-C, chondroitin sulfate proteoglycans and glial fibrillary acidic protein in astrocytes in the LPC-induced model of inflammation. The level of myelin protein in neurites and oligodendrocyte cell bodies was significantly upregulated by GA and VA treatment. The reduction in sustained repetitive firing in the LPC-induced model of inflammation was reversed by both GA and VA treatment. This study supports the hypothesis that VA and GA have anti-inflammatory activities and could be regarded as potential treatments for neurodegenerative disease.

Vitex negundo induces an anticonvulsant effect by inhibiting voltage gated sodium channels in murine Neuro 2A cell line.

Vitex negundo (Vn) extract is famous for the treatment of neurological diseases such as migraine and epilepsy. These neurological diseases have been associated with abnormally increased influx of sodium ions into the neurons. Drugs that inhibit voltage gated sodium channels can be used as potent anti-epileptics. Till now, the effects of Vn on sodium channels have not been investigated. Therefore, we have investigated the effects of methalonic fraction of Vn extract in Murine Neuro 2A cell line. Cells were cultured in a defined medium with or without the Vn extract (100 µg/ml). Sodium currents were recorded using whole-cell patch clamp method. The data show that methanolic extract of Vn inhibited sodium currents in a dose dependent manner (IC50 =161µg/ml). Vn (100 µg/ml) shifted the steady-state inactivation curve to the left or towards the hyper polarization state. However, Vn did not show any effects on outward rectifying potassium currents. Moreover, Vn (100 µg/ml) significantly reduced the sustained repetitive (48±4.8%, P<0.01) firing from neonatal hippocampal neurons at 12 DIV. Hence, our data suggested that inhibition of sodium channels by Vn may exert pharmacological effects in reducing pain and convulsions.

Immunomodulatory activity and chemical characterization of fixed oils obtained from different parts of Oxytropis glabra DC.

Oxytropis glabra DC. is a plant with enormous therapeutic vitality. In the present study a comparison of lipophilic profiling of different parts of O. glabra has been carried out by using gas chromatography-mass spectrometry. A total of 32 compounds have been identified from this plant, amongst which 31 have been identified for the first time. These compounds have been further confirmed from their Van den Dool and Kratz (I) Indices. Out of these 32 compounds, 18 have been identified from flower (80.94%), 15 from fruit (85.36%), 11 from leaves (66.35%) and 11 from root (45.96%). The major class of metabolite identified from different parts is fatty acid. Hydrocarbons have also been detected in flower and fruit but not in root and leaves. The extracts were screened for their immunomodulatory activity on whole blood cells. The root oil was found to be moderately active (IC50 32.3 µg/mL). At present only limited data is available on the phytochemical composition of O. glabra.

Synthesis, characterization and SAR of novel Bezimidazole derivatives as Nematicidal agents.

Six novel analogues were prepared by reacting benzimidazole molecules (BM and CMB) propiophenone and benzoyl chlorides respectively. The structures of newly synthesized compounds were determined with the help of spectroscopic techniques. The compounds were subjected to in-vitro screening for their activity against nematodes. It was observed that the benzimidazole (BM) derivatives possessed more nematicidal activity as compared to that of cyanomethyl-benzimidazole (CMB) for Meloidogyne incognita. Among them, the propiophenone substituted benzimidazole derivative B3 was found to be the most active compound and can be further studied as lead molecule for development of anthelmintic drugs.

Neurite outgrowth properties of Calotropis procera: In search for a neuroprotectant.

In view of the well-documented medicinal properties of Calotropis procera (CP), the present study was designed to evaluate the neuroprotective effect of the extract. We have prepared a methanolic extract of Calotropis procera and screen varying concentration of CP (20, 30, 40, 50 and 70µg/ml) for the stimulatory potency on neurite outgrowth. The stimulatory effect of CP on neurite outgrowth was assessed in primary hippocampal neurons. Neurite lengths were measured using optika provison analysis software. Neuritogenesis was further analyzed by immunostaining by using specific neuronal marker ß III-tubulin. The data show that neurite outgrowth from hippocampal neurons were significantly enhanced in the presence of CP (40µg/ml). The most stimulatory neurite outgrowth effects were appeared after 48hrs incubation of neurons with CP (40µg/ml). These data confirm that CP extract could promote invitro hippocampal neurite outgrowth in a dose-dependent manner. Our results indicate that CP can be used as a healthy dietary supplement for the cognitive functions of the brain.

Neuroprotective capabilities of Vitex negundo in primary hippocampal neurons.

Vitex negundu (Vn) is a well-known aromatic shrub commonly used as a traditional folk medicine famous for its potential pharmacological and biological activities. Several chemical compounds are extracted and identified from the different parts of the Vn such as leaves, root, seeds and flowers. Number of researches reported the herb as antimicrobial, anti-androgenic, anti-osteoporotic, and anti-tumour, anti-cancer, anti-inflammatory, anti-oxidant, anti-hyperglycemic and hepatoprotective. The effects of Vn on neurite outgrowth have not been identified till now. Therefore present study was designed to investigate the neurite outgrowth effects of Vn extract in hippocampal neurons. Neurons from P0 mice were isolated and cultured in defined medium containing the different concentrations of Vn (20, 30, 40, 50, 100, 150 and 200 µg/ml) for 48 hrs. The presence of the neurites was confirmed by using ßIII-tubulin antibody which specifically labels only the neurites. Morphometric analysis was done by using Optika Pro-Vision software. The data show that Vn at 30 and 40 µg/ml significantly increased the mean average length of the longest neurite whereas at 150 and 200 µg/ml it significantly decreased the mean average length of the 10 longest neurite in hippocampal neurons. Nevertheless Vn did not show any significant effects on the sum of all the neurite lengths at any concentrations tested. Taken together the result shows that methanolic extract of Vn has potential to produce long neurites at 30 and 40 µg/ml and therefore can be act as a neuroprotective agent in the future drug development.

Antimicrobial and antioxidant screening of N¢-substituted sulphonyl and benzoyl derivatives of 4-Pyridine carboxylic acid hydrazide.

In this research program, the antibacterial, antifungal and antioxidant activities of six N'-substituted sulfonyl and benzoyl derivatives of lead molecule PCH were reported. Out of these compounds, sulphonyl derivatives 2,3 and benzoyl derivative 5 showed moderate to good activity against different strains of gram-positive and gram-negative bacteria including B. cereus, B. subtilis, B. thruingiensis and S. pyogenes, S. fecalis and E. coli ATCC 8739. Moreover, upon antifungal screening, the compound, N¢-[(2,4,6-trimethylbenzene) sulfonyl]pyridine-4-carbohydrazide possessed good antifungal activity against Candida species, a causative agent of systemic fungal infections. Antioxidant study demonstrated more than 50% inhibition in DPPH assay for sulphonyl derivative 2 indicating its potential as antioxidant while the other derivatives expressed low level of radical scavenging property.

Enzymatic biotransformation of terpenes as bioactive agents.

The plant-derived terpenoids are considered to be the most potent anticancer, anti-inflammatory and anticarcinogenic compounds known. Enzymatic biotransformation is a very useful approach to expand the chemical diversity of natural products. Recent enzymatic biotransformation studies on terpenoids have resulted in the isolation of novel compounds. 14-hydroxy methyl caryophyllene oxide produced from caryophyllene oxide showed a potent inhibitory activity against the butyryl cholinesterase enzyme, and was found to be more potent than parent caryophyllene oxide. The metabolites 3ß,7ß-dihydroxy-11-oxo-olean-12-en-30-oic acid, betulin, betulonic acid, argentatin A, incanilin, 18ß glycyrrhetinic acid, 3,11-dioxo-olean-12-en-30-oic acid produced from 18ß glycyrrhetinic acid were screened against the enzyme lipoxygenase. 3,11-Dioxo-olean-12-en-30-oic acid, was found to be more active than the parent compound. The metabolites 3ß-hydroxy sclareol 18α-hydroxy sclareol, 6α,18α-dihydroxy sclareol, 11S,18α-dihydroxy sclareol, and 1ß-hydroxy sclareol and 11S,18α-dihydroxy sclareol produced from sclareol were screened for antibacterial activity. 1ß-Hydroxy sclareol was found to be more active than parent sclareol. There are several reports on natural product enzymatic biotransformation, but few have been conducted on terpenes. This review summarizes the classification, advantages and agents of enzymatic transformation and examines the potential role of new enzymatically transformed terpenoids and their derivatives in the chemoprevention and treatment of other diseases.

Behavioral and neurochemical profile of some novel phenacyl based isonipecotamide derivatives.

Study of natural products led to the development of new molecules of potential biological activity. Piperidine nucleus constitutes one of the components of various alkaloids and drugs. During the course of our project regarding the synthesis of derivatives of piperidine carboxamide to study the effects of these compounds as anti-depressive agents, some of the compounds exhibited significant effects at all three doses, through open field activity thus establishing a direct relationship between dose and locomotion. Moreover, these compounds have also shown the decreased level of 5-HT alone with increased level of dopamine as an indication of their antagonism towards 5-HT receptor.

Crystal structure and Hirshfeld surface analysis of 3-octyl-4-oxo-2,6-bis-(3,4,5-tri-meth-oxy-phen-yl)piperidinium chloride.

The title compound, C31H46NO7+·Cl-, was synthesized by a one-pot Mannich condensation reaction. In the mol-ecule, the piperidinone ring adopts a chair conformation, and the trimeth-oxy-substituted benzene rings and octyl chain are arranged equatorially. In the crystal, centrosymmetric dimers are linked into layers parallel to (011) by N-H⋯Cl and C-H⋯Cl hydrogen bonds. A Hirshfeld surface analysis indicates that the most important contributions for the crystal packing are O⋯H (20.5%) inter-actions followed by C⋯H (7.8%), Cl⋯H (5.5%), C⋯C (1.2%), C⋯O (0.5%) and Cl⋯O (0.4%) inter-actions.

Synthesis and smooth muscle-selective relaxant activity of a piperidine analogue: 1-(4'-fluorophenacyl)-4-hydroxy-4-phenyl-piperidinium chloride.

The antispasmodic and vasodilator activities of a newly synthesized piperidine derivative (1-(4'-fluorophenacyl)-4-hydroxy-4-phenyl-piperidinium chloride) were studied in vitro. The test compound exhibited a dose-dependent relaxant effect on the spontaneous and K+ (75 mM)-induced contractions of isolated rabbit jejunum with respective EC50 values of 0.01 mM (0.01-0.02, 95% Cl) and 0.30 mM (0.17-0.56). The Ca++ channel blocking (CCB) activity was confirmed when the test compound (0.1-0.2 mM) shifted the Ca++ dose-response curves to the right, similar to that produced by verapamil (0.1-1.0 microM), a standard CCB. In the isolated rabbit aorta, the test compound showed a dose-dependent vasodilator effect on K+ (75 mM)-induced contractions with an EC50 value of 0.08 mM (0.02-0.26) while also suppressed the norepinephrine (1 microM) control peak responses with EC50 value of 0.08 mM (0.05-0.13, n=5). When tested in Langendorff perfused rabbit heart preparation, the test compound exhibited a negligible inhibitory effect on the rate or force of atrial and ventricular contractions when tested up to 5 mM. The results show smooth muscle-selective relaxant effect of the test compound on intestinal and vascular preparations mediated possibly via blockade of voltage and receptor-operated Ca++ channels.

Two new triterpenes from Alstonia scholaris flowers.

In the context of our previous communication on phytochemical studies of the ethanolic extract of flowers of Alstonia scholaris of Pakistan origin, these have resulted in the isolation of two new triterpenoids. One is of the oleanane type, alstoprenyol, 3-ß-hydroxy-28-ß-acetoxy-5-olea triterpene (1), the other is of ursane type, alstoprenylene 3ß-acetate-24-nor-urs-4,12,2'-triene ester triterpene (2) and together with four known triterpenes, α-amyrin acetate (3), α-amyrin (4), lupeol acetate (5) and 3ß-hydroxy-24-nor-urs-4,12,28-triene triterpene (6) were isolated. The structures of 1-6 were elucidated with the aid of extensive NMR spectroscopic studies.

Malaria and artemisinin derivatives: an updated review.

Malaria is the world's most prevalent disease that affects 515-600 million people each year and about 40% of the world's population live at risk for this infection. The prevalence of morbidity and mortality from drug resistant malaria (Plasmodium falciparum) is increasing in most of the developing countries, which is also a global threat because international travel is common now and imported malaria is increasingly a serious problem. Since rapid schizonticidal action of naturally occurring endoperoxides pharmacophore present in artemisinin against drug-resistant malaria has been documented, researchers have focused more on artemisinin analogs than any other antimalarials. In this review, drugs of choice about malaria i.e. artemisinin and its analogus/derivatives (arteether, artemether, artemiside, artemisinin, artemisone, artesunate, dihydroartemisinin) have been discussed in detail e.g. bioavailability, formulation development, stability, combination therapy, additional benefits, drug resistance and toxicity have been reviewed.

Naturally occurring and synthetic agents as potential anti-inflammatory and immunomodulants.

Terpenes in general and triterpenes in particular showed anti-inflammatory activity and act as immunomodulators in nutraceutical agents. Antiinflammation, a useful and attractive approach in experimental oncology, helps to investigate the inflammation preventive potential of natural products and synthetic entities. During the course of our research work in natural product chemistry and synthesis of novel structures in the field of heterocyclic chemistry, we found interesting results. In natural product betulinic acid, α-amyrin acetate, lupeol acetate, oleanolic acid, ursolic acid and their derivatives showed interesting potential analgesic and anti-inflammatory activity. In this review specific reference has been made to novel classes and newly discovered compounds in the literature, which exhibited required activities. Indomethacine is a potent synthetic compound, which becomes the basis of novel anti-inflammatory agents. Shen postulated a receptor theory which indicates the physical parameters responsible for anti-inflammatory activity. Attempt has been made to cover almost all the anti-inflammatory agents which fall under the various chemical structural classes of compounds showing required activity. The objective of this review is to compile relevant data on the mechanism of action of terpenes isolated from active ethnomedicinal plants to examine the role terpenoids have in medicinal plants used against inflammatory diseases, especially those in which an immune response is implicated. In addition, a selection of several structurally related compounds has been compiled in order to analyze the possible structural characteristics and relationships between the different types of structures found in triterpenoids. The selection of active species was made on the basis of their immunomodulatory activity, and their role in the resolution of diseases in which the immune system is implicated to examine the mechanism by which they are useful as ethnopharmacological medicines. These terpenes include ursolic acid, oleanolic acid, betulinic acid. This review discusses in detail the preclinical studies conducted with triterpenes and provides an insight into its mechanism of action.

Investigation of piperidine derivatives in ex vivo models of pain and platelet aggregation.

Piperidine derivatives are known to exhibit analgesic activities and are likely to possess the ability to block the effects of prostaglandins through inhibition of downstream signaling pathways. The present study investigated the activity of five derivatives (PD2-6) of 4-(4'-bromophenyl)-4-piperidinol (PD1), against pain and platelet aggregation mediated by the release of prostaglandins and thromboxane A2, respectively. The results showed that compound PD1 and its two phenacyl derivatives PD3 and PD5 exhibited a highly significant analgesic effect (p < 0.01), whereas PD4 and PD6 also showed significant activity. PD3, the most active analgesic compound when docked to the opioid receptor, had interactions between the oxygen of its nitro group and the amino group of ARG 573, indicating a distance of 1.2563 Å. The antiplatelet data showed that compound PD5 (4-(4'-bromo-phenyl)-4-hydroxy-1-[2-(2″,4″-dimethoxyphenyl)-2-oxo-ethyl]-piperidinium bromide) had an IC(50) = 0.06 mM, which was the most active compound, whereas PD3 was the second most active compound against platelet aggregating factor-induced aggregation with an IC(50) = 80 mM. Acetyl salicylic acid (IC(50) = 150 µM) was used as a positive control.

Leishmanicidal potential of N-substituted morpholine derivatives: synthesis and structure-activity relationships.

A series of N-substituted morpholines 2-20 was synthesised by reacting various acid chlorides and alkyl halides with morpholine (1). All of the synthesised compounds 2-20 were screened for their leishmanicidal effects using amphotericin B (IC(50) = 0.24 microg L(-1)) and pentamidine (IC(50) = 2.56 microg mL(-1)) as standards and a structure-activity relationship (SAR) study was established. The compounds 2 (IC(50) = 48 microg mL(-1)), 3 (IC(50) = 30.0 microg mL(-1)), 10 (IC(50) = 41.0 microg mL(-1)), 15 (IC(50) = 33.0 microg mL(-1)), 16 (IC(50) = 35.0 microg mL(-1)) and 20 (IC(50) = 47.0 microg mL(-1)) showed weak leishmanicidal activities.

Synthesis and pharmacological activity of 4-(4'-(chlorophenyl)-4-hydroxypiperidine) derivatives.

A new series of 4-(4'-chlorophenyl)-4-hydroxypiperidine derivatives (2-5), substituted at nitrogen, were synthesized and tested as potential analgesic compounds as well as evaluated for their effect on hypotensive activity. Results showed that all the derivatives exhibit significant analgesic activity in male Wistar rats at a dose of 50 mg/kg of body weight after intramuscular injection, when tested by thermal stimuli (tail flick test). Pethidine was used as reference drug. Compounds 2, 3 and 5 produced reduction in blood pressure in normotensive rat.

Syntheses, antibacterial, cytotoxic and antifungal effects of new 3-carboxy-l-phenacylpyridinium salts.

Thirteen pyridine-3-carboxylic acid salt derivatives with various substituted phenacyl residues were prepared and their cytotoxicity, antibacterial and antifungal activities tested. Compounds 5 and 11 proved to be active in the brine shrimp bioassay, compounds 7, 9-12 and 14 showed promising antibacterial activities, whereas none of the compounds tested against 15 fungal cultures proved to be active. Extensive spectroscopic techniques were employed to confirm the structure of the synthetic products.