A novel phytochemical from Dipteris wallichii inhibits human ß-secretase 1: Implications for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent progressive neurodegenerative disease, and the most common cause of dementia. One of the histopathological hallmarks of AD is the accumulation of extracellular amyloid-ß (Aß) oligomers as neuritic plaques in brain. The Aß oligomers are produced from amyloid precursor protein by the action of secretase enzymes, among which ß-secretase 1 (BACE1) catalyses the rate-limiting step. Thus, BACE1 is one of the most important therapeutic targets in preventing deposition of the plaques, progression of the disease, and thus as a disease-modifying therapeutic strategy. The present study was undertaken to isolate and identify novel phytochemicals from the pteridophyte Dipteris wallichii, and to determine their pharmacological properties. A novel compound was eventually detected and named Dip-1, and its pharmacological properties were predicted using computational modelling. The compound was found to have pharmacophores similar to those of known BACE1 inhibitors. Thus, further studies were performed to determine its drug likeness, blood-brain barrier (BBB) permeability, inhibitory potential and IC50 value. The results were promising, and the compound was found to have high drug likeness and BBB permeability, and a potent inhibitor of BACE1, with IC50 value of 0.0372 nM. Thus, the present study reports a novel BACE1 inhibitor from the plant D. wallichii, and is significant owing to its therapeutic implication as a disease-modifying therapy for AD.

In silico modelling of azole derivatives with tyrosinase inhibition ability: Application of the models for activity prediction of new compounds.

Tyrosinase is a metal containing multifunctional enzymes found in animals, fruits and vegetables and constitutes the primary cause for diseases resulting from overproduction of melanin as well as for browning of fruits. Inhibitors of the enzyme have thus gained increased importance in food and cosmetic industry. In the present work, a group of azole derivatives with tyrosinase inhibitory activity were explored to analyse the prime structural attributes of the potent inhibitors. In silico models have been developed in order to have a close insight regarding features of the molecular fragments that may affect the activity of the molecules conducively. The biological pharmacophore of the inhibitors that accounts for their interaction with the tyrosinase enzyme has been ascertained based on the development of a 3D pharmacophore model. The models thus developed were subsequently utilised for screening a set of compounds that were previously synthesised in-house and were reported to possess antioxidant activity. The final selection of active molecules in the screening process was done based on the docking interactions of the molecules with the tyrosinase enzyme and assessment of their degree of binding to the protein. Thus the developed models have been successfully utilised for identifying active compounds from a series of untested molecules.

Quantitative Analysis of Essential Molecular Features of Coumarin Derivatives with Antioxidant Activity Using Chemometric Tools.

BACKGROUND: The endogeneous antioxidant mechanism often fails to combat the huge free radical overload necessitating external antioxidant supplementation. Thus identification and definite structural manipulation of the naturally available antioxidant derivatives using in silico methodology help to design new moieties with improved therapeutic potential. OBJECTIVE: The present work has been performed with the aim to identify the essential molecular fragments that contribute to the antioxidant property of the coumarin derivatives. METHOD: In this work three separate chemometric methods were utilised to highlight the structural requisites of the coumarin derivatives. RESULTS: The QSAR model thus developed helps to highlight the prime molecular fragments, while the 3D pharmacophore model denotes the features constituting the biological pharmacophore for the coumarin derivatives. Again, the HQSAR contour signifies the relative contribution of the different molecular fragments. CONCLUSION: In silico techniques thus adapted in the present work highlight a significant paradigm in the process of screening and designing therapeutically active antioxidant moieties.

Synthesis and biological evaluation of some novel furan derivatives.

The present work involved cyclization of Schiff bases to azetidine-2-one and thiazolidine 4-one derivatives. The schiff bases (IIIa-j) were obtained upon reaction between electrophillic carbon atom of furfuraldehyde and nucleophillic nitrogen atom of amines. Azetidine-2-one derivatives (IVa-j) were obtained by reaction between imines and monochloro acetyl chloride in the presence of triethyl amine and 1, 4 dioxan. On the other hand, preparations of thiazolidine-4-ones (Va-j) were preceded by nucleophilic attack of sulphur of thioglycolic acid on imine carbon followed by intramolecular cyclization in the presence of SnCl2. The structures of the compounds were confirmed by spectral and elemental analysis. The biological evaluation of the compounds like anti-microbial, antioxidant, analgesic, CNS depressant and anti-diabetic activity were determined. From the pharmacological investigation it was found that out of all the compounds IVa, IVb, IVe, IVf, IVh,Va, Vb, Ve, Vf, Vh had shown more potent activity.

Cisplatin-induced nephrotoxicity in mice: protective role of Leea asiatica leaves.

Cisplatin is a popular anticancer drug, but its side effects like nephrotoxicity and hepatotoxicity due to oxidative stress limited its clinical use. In tis study, nephoprotective effect of fractions of Leea asiatica (Leeaceae) leaves was assessed against cisplatin induced toxicity in rats. Leaves of L. asiatica extracted with methanol, ethyl acetate, petroleum ether, and evaluated for in vitro and ex vivo antioxidant activity using several assay models. Methanol extract showed better antioxidant effects, and contain higher amount of phenolic (77.75 ± 0.87 mg GAE/g of dry material) and flavonoid compound (60.98 ± 0.58 mg QE/g of dry material) compared with other extracts. Hance methanol extract was selected for further investigation and fractionated with methanol, ethyl acetate, petroleum ether. Protective effect of methanol extract and its fractions was evaluated against cisplatin (20 mg/kg, i.p.) induced nephrotoxicity. Pretreatment with methanol extract (150 and 300 mg/kg), and its fractions especially methanol, ethyl acetate fraction (75 and 150 mg/kg) significantly reduced blood urea nitrogen, serum creatinine, uric acid levels, and decreased malondialdehyde level and increase total protein and albumin level (p < 0.05, 0.01). Ethyl acetate fraction produced highest nephroprotective, possibly by inhibiting lipid peroxidation process. Result suggested that ethyl acetate fraction possesses potent nephroprotective activity and can be used an adjunct therapy aiming to improve the effectiveness of several nephrotoxic drugs.

Total phenolic, total flavonoid content, and antioxidant capacity of the leaves of Meyna spinosa Roxb., an Indian medicinal plant.

AIM: The objective of the present study was to determine the total phenolic and total flavonoid contents, and to evaluate the antioxidant potential of different leaf extracts of Meyna spinosa Roxb. ex Link, a traditional medicinal plant of India. METHODS: Free radical scavenging and antioxidant potential of the methanol, ethyl acetate, and petroleum ether extracts of Meyna spinosa leaves were investigated using several in vitro and ex vivo assays, including the 2, 2-diphenyl-picrylhydrazyl radical scavenging, superoxide anion scavenging, hydroxyl radical scavenging, nitric oxide radical scavenging, hydrogen peroxide scavenging activity, metal chelating assay, and reducing power ability method. Total antioxidant activity of the extracts was estimated by the ferric thiocyanate method. Inhibition assay of lipid peroxidation and oxidative hemolysis were also performed to confirm the protective effect of the extracts. Total phenolic and total flavonoid contents of the extracts were estimated using standard chemical assay procedures. RESULTS: Methanol extracts showed the highest polyphenolic content and possessed the better antioxidant activity than the other two extracts. Total phenolic and total flavonoid contents in the methanol extract were (90.08 ± 0.44) mg gallic acid equivalents/g and (58.50 ± 0.09) mg quercetin equivalents/g, respectively. The IC50 of the methanol extract in the DPPH(·), superoxide anion, hydroxyl radical, nitric oxide radical, hydrogen peroxide scavenging activity and metal chelating assays were (16.4 ± 0.41), (35.9 ± 0.19), (24.1 ± 0.33), (23.7 ± 0.09), (126.8 ± 2.92), and (117.2 ± 1.01) µg·mL(-1), respectively. The methanol extract showed potent reducing power ability, total antioxidant activity, and significantly inhibit lipid peroxidation and oxidative hemolysis which was similar to that of standards. CONCLUSION: The results indicated a direct correlation between the antioxidant activity and the polyphenolic content of the extracts, which may the foremost contributors to the antioxidant activity of the plant. The present study confirmed that the methanol extract of Meyna spinosa leaves is a potential source of natural antioxidants.

Antitussive, expectorant activity of Marsilea minuta L., an Indian vegetable.

Marsilea minuta L., an aquatic or sub-aquatic fern used as a vegetable, has wide applications in traditional/folk medicine in India and Bangladesh. In our study, we evaluated the antitussive, expectorant activity of M. minuta crude extracts. The antitussive activity of M. minuta methanol, ethyl acetate, and petroleum ether extracts was evaluated using ammonia and sulfur dioxide induced mice coughing. The expectorant activity was evaluated by the volume of phenol red in mice's tracheas. Extracts significantly increased mice's cough latent period and inhibited the frequency of cough induced by ammonia and sulfur dioxide, and improved tracheal phenol red output in expectorant evaluation. Methanol extract produced the highest activity in all tested models. Methanol extract at 500 mg/kg showed 59.5% and 55.8% inhibition in the number of coughing induced by ammonium liquor and SO2, respectively, while it showed 89.3% increase in phenol red secretion at the same dose, which showed superior activity compared to other extracts. The present study provided evidence for M. minuta to be used as an antitussive and expectorant in Indian folk medicine.

Anthelmintic and in vitro antioxidant evaluation of fractions of methanol extract of Leea asiatica leaves.

Leea asiatica, a folk medicinal plant of India, is used in the treatment of worm infection and other oxidative stress-related disorders, traditionally. In the present study, the in vitro anthelmintic and in vitro antioxidant activity of different fractions of the methanol extract from the Leea asiatica leaves were evaluated. The fraction displayed significant anthelmintic activity against Indian adult earthworms (Pheretima posthuma). The ethyl acetate fraction showed a better paralysis activity (13.99 ± 0.59), while the methanol fraction showed a better death time (63.76 ± 0.73 minutes), when compared with other fractions, at a dose of 50 mg/ml concentration. The anthelmintic activity of methanol and the ethyl acetate fraction were almost similar and comparable to the standard drug, piperazine citrate. The petroleum ether fraction did not produce a potent anthelmintic effect compared to the standard. The in vitro antioxidant activity was evaluated by using the diphenyl-picrylhydrazyl (DPPH) radical scavenging assay, nitric oxide radical scavenging assay, lipid peroxidation assay, and the ferric thiocyanate method. The ethyl acetate fraction showed better antioxidant activity in all tested methods. The IC(50) value of the ethyl acetate fraction in the DPPH radical, nitric oxide radical scavenging assay, and lipid peroxidation assay were 9.5, 13.0, and 57.0 µg/ml, respectively. The fractions significantly (P < 0.05) inhibited the peroxidation of linoleic acid. The results confirmed the folk use of Leea asiatica in warm infection and the plant could be viewed as a potential source of natural anthelmintic and antioxidant compound.

Synthesis of some oxazolinones and imidazolinones and their antimicrobial screening.

A few imidazolinones [1-aminoethyl/phenyl-2-methyl/phe- nyl-4-acetylidene/benzylidene-imidazolin-5[4H]-ones] were newly synthesized from respetive acetylidene/benzylidene oxazolinones. Schiff's bases were synthesized by the reaction between imidazolinones and benzaldehyde. The antimicrobial screening of almost all compounds showed moderate to significant activities against B. subtilis ATCC 6633 and K. pneumoniae ATCC 25063. Compounds 10 [1-aminophenyl-2-phenyl-4-acetylidene-imidazolin-5[4H]-one] and 12 [1-aminophenyl-2-phenyl-4-benzylidene-imi- dazolin-5[4H]-one] showed even better activity than amphotericin B against C. albicans ATCC 29738.