Sukhbir Lal Khokra

Synthesis of some novel N4-(naphtha[1,2-d]thiazol-2-yl)semicarbazides as potential anticonvulsants.

A series of N(4)-(naphtha[1,2-d]thiazol-2-yl)semicarbazides were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure tests and minimal motor impairment was determined by rotorod test. A majority of the compounds exhibited significant anticonvulsant activity after intraperitoneal administration. Some of the selected compounds were evaluated orally in rats for activity in scPTZ test at several time points (50 mg/kg). The most active compounds carry bromo, fluoro and nitro substituents at 4-position in the phenyl ring. The biochemical estimations of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) from brain homogenate not only clearly implicated the role of free radicals in PTZ-induced convulsion but also explained the possible mechanism of protective effect of semicarbazides, through the reduced formation of MDA and increased formation of SOD and GSH-Px.

Pharmacophore Modeling and Molecular Docking Studies on Pinus roxburghii as a Target for Diabetes Mellitus

The present study attempts to establish a relationship between ethnopharmacological claims and bioactive constituents present in Pinus roxburghii against all possible targets for diabetes through molecular docking and to develop a pharmacophore model for the active target. The process of molecular docking involves study of different bonding modes of one ligand with active cavities of target receptors protein tyrosine phosphatase 1-beta (PTP-1β), dipeptidyl peptidase-IV (DPP-IV), aldose reductase (AR), and insulin receptor (IR) with help of docking software Molegro virtual docker (MVD). From the results of docking score values on different receptors for antidiabetic activity, it is observed that constituents, namely, secoisoresinol, pinoresinol, and cedeodarin, showed the best docking results on almost all the receptors, while the most significant results were observed on AR. Then, LigandScout was applied to develop a pharmacophore model for active target. LigandScout revealed that 2 hydrogen bond donors pointing towards Tyr 48 and His 110 are a major requirement of the pharmacophore generated. In our molecular docking studies, the active constituent, secoisoresinol, has also shown hydrogen bonding with His 110 residue which is a part of the pharmacophore. The docking results have given better insights into the development of better aldose reductase inhibitor so as to treat diabetes related secondary complications.

Structure based designing and ADME-T studies of butenolide derivatives as potential agents against receptor ICAM-1: A drug target for cerebral malaria

Abstract An attempt toward designing of some butenolide derivatives against Cerebral Malaria (CM), as inhibitors of Intercellular adhesion molecule- 1(ICAM-1) was carried out using in silico approaches of molecular docking studies. ADME-T studies were also performed to further optimize the ligands. Binding conformations were compared with Artesunate, the main drug used in treatment of CM, the designed ligands exhibited comparative binding with artesunate. Finally the whole effort leads to total nine most promising analogues ( 1c , 2b , 2c , 2d , 2h , 3c , 3d , 3i and 4d ) which can be explored further as a template to design more potential agents against cerebral malaria.

Bioassay Guided Fractionation and ñ-Amylase Inhibitory Activity ofFlavanoid Isolated from Pinus roxburghii Sarg.

Pinus roxburghii Sarg. is a traditional plant used in the treatment of diabetes mellitus ethnopharmacology in India and Africa. In this written report, we looked into the antidiabetic activity using α-amylase inhibitory assay on extracts from the bark of Pinus roxburghii Sarg. by bioassay guided fractionation. The ethanol extract (43.4% inhibition) and the isolated compound (49.6% inhibition) exhibited significant enzyme inhibitory activity against α-amylase. This is reported, from this plant, for the first time. The 1H and 13C NMR, IR and mass spectral studies of isolated compound suggested it as quercetin. Our study revealed, for the first time, the isolation and α-amylase inhibitory activity of quercetin from Pinus roxburghii Sarg. bark.

Anticonvulsant activity of essential oils isolated from Vitex negundo Linn

The essential oils isolated from dried fruits, fresh leaves and flowers of Vitex negundo Linn. were compared with phenytoin in MES and diazepam in PTZ induced seizures methods. Fruit oil showed good protection against PTZ induced clonic convulsions and reduced the extensor phase duration in MES. The essential oil of leaves showed excellent protection in mice against PTZ induced clonic convulsions only. The subprotective doses of all the oils (100 mg kg, p.o) potentiated the anticonvulsant action of phenytoin and diazepam. These oils may be used in adjuvant therapy along with standard anticonvulsants and can possibly lower the requirements of phenytoin and diazepam.

Quinoline based furanones and their nitrogen analogues: Docking, synthesis and biological evaluation

A small library of twenty-four quinoline based butenolides also known as furanones and their nitrogen analogues was prepared by using two different aroylpropionic acids, viz. 3-(2-naphthoyl)propionic acid (3) and 3-(biphenyl-4-yl)propionic acid (4), as starting materials. The 3-aroylpropionic acids were reacted with different 6-substituted-2-chloroquinolin-3-carbaldehydes (2a–d) to obtain the corresponding furan-2(3H)-ones (5a–h). The purified and characterized furanones were then converted into their corresponding 2(3H)-pyrrolones (6a–h) and N-benzyl-pyrrol-2(3H)-ones (7a–h). The antimicrobial activities of the title compounds were evaluated against two strains of each Gram +ve (Staphylococcus aureus and Bacillus subtilis), Gram −ve bacteria (Escherichia coli and Pseudomonas aeruginosa) and against fungal strains of Aspergillus niger and Aspergillus flavus. In vivo anti-inflammatory potential of the title compounds was investigated by standard method. Majority of the compounds showed significant antibacterial activity against both the Gram +ve strains. Eight most potent anti-inflammatory compounds (5b, 5d, 5h, 6b, 7b, 7d, 7f, 7h) which exhibited >53% inhibition in edema, were also screened for their in vivo analgesic activity. All the tested compounds were found to have significant reduction in ulcerogenic action but only three compounds (5d, 5h and 7h) showed comparable analgesic activity to standard drug, diclofenac. The results were also validated using in silico approach and maximum mol doc score was obtained for compounds 7a–h. On comparing the in vivo and in silico anti-inflammatory results of synthesized compounds, N-benzyl pyrrolones (7a–h) emerged as the potent anti-inflammatory agents. It was also observed that compounds that possess electron withdrawing group such as —Cl or NO2 are more biologically active.

Rational Design and Synthesis of Biologically Active Disubstituted 2(3H) Furanones and Pyrrolone Derivatives as Potent and Safer Non Steroidal Anti-inflammatory Agents

BACKGROUND Furanone and pyrrolone heterocyclic ring system represent important and interesting classes of bioactive compounds. Medicinal chemists use these heterocycyclic moieties as scaffolds in drug design and discovery. METHODS A series of 3-arylidene-5-(naphthalene-2-yl)-furan-2(3H)-ones (2a-j) were synthesized by incorporating pharmacophore of COX-2 inhibitor rofecoxib and naphthyl ring of naproxen as potential non steroidal anti-inflammatory agents. These furanone derivatives were subsequently reacted with dry ammonia gas and benzylamine to furnish corresponding 3-arylidene-5-(naphthlen-2-yl)-1H-pyrrol-2(3H)-ones (3a-e) and 3-arylidene-1-benzyl-5- (naphthalene-2-yl)-1H-pyrrol-2(3H)-ones (4a-e), respectively. The newly prepared heterocyclics were screened for their expected in-vivo biological activities including anti-inflammatory, analgesic and ulcerogenic actions in rodents. The COX-2 inhibitory behavior of synthesized compounds was also assessed via automated docking studies. RESULTS The chemical structure of the synthesized compounds was characterized by using modern spectroscopic techniques. Result of in-vivo pharmacological studies demonstrated that almost all N-Benzyl-pyrrol-2(3H)-ones (4a-e) showed better anti-inflammatory and analgesic activities in comparison with the other two series of furan-2(3H)-ones and pyrrol- 2(3H)-ones. The moldock score value of the tested compounds was found in the range of -116.66 to -170.328 and was better than the standard drug. CONCLUSION Among all the synthesized compounds, only nine compounds (2d, 2g, 2h, 3d, 4a, 4b, 4c, 4d and 4e) exhibited potent anti-inflammatory and analgesic activities with significantly reduced gastrointestinal toxicity in various animal models in comparison to standard drug, diclofenac. Therefore, it is recommended to explore the potential of the synthesized compounds as lead candidates for the development of new therapeutic agents.

Pharmacophore modeling studies on N-hydroxyphenyl acrylamides and N-hydroxypyridin-2-yl-acrylamides as inhibitor of human cancer leukemia K562 cells

In order to understand the essential structural features for inhibitors of human cancer leukemia K562 cells, three-dimensional pharmacophore hypotheses were built on the basis of a set of inhibitors of human cancer leukemia K562 selected from literature using PHASE program. Five point pharmacophore with two hydrogen bond acceptor (A), one hydrogen bond donor (D), and two aromatic rings (R) as pharmacophoric features were developed. Among them, the pharmacophore hypothesis AADRR 62 yielded a statistically significant 3D-QSAR model with as R2 value 0.883 and Q2 value 0.528 and was considered to be the best pharmacophore hypothesis. The developed pharmacophore model was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.765 was observed between experimental and predicted activity values of test set molecules.

A STUDY ON NEUROLOGICAL SIGNIFICANCE OF VITEX NEGUNDO LINN.

The main purpose of this study was to evaluate antioxidant and anticonvulsant activity and to establish relation between two. The putative anticonvulsant activity of essential oils and ethanolic extracts of fruits, flowers, leaves and roots of Vitex negundo was evaluated using maximal electroshock seizures and pentylenetetrazole methods while antioxidant potential was studied using DPPH and ferric reducing assay. Ethanolic extracts of fruits, leaves, flowers and roots abolished tonic MES-induced convulsions in 40 % of test animals and reduced the mortality rate to 50 %. The leaves extract at the doses of 250 and 500 mg/kg p.o. produced significant decrease in duration of clonic phase and abolished the clonic phase in 60 % and 70 % of animals respectively in PTZ model. The simultaneous administration of ethanolic extract of leaves and fruit with diazepam at sub-protective doses abolished clonic phase duration significantly. Antioxidant studies showed that most of essential oils and ethanolic extracts of V. negundo showed significant antioxidant activity in both DPPH and ferric reducing power methods. The essential oils of leaves, flower and dry fruit showed significant antioxidant activity along with methanolic and ethanolic extract of leaves. So, it is concluded that essential oils as well as extracts especially leaves have strong antioxidant potential. These results indicate that V. negundo may be further explored for their use as effective anticonvulsant, which may be attributed to antioxidant properties.