In vivo pharmacological profile of substituted (3-pyridyl)-2-phenylisoxazolidine analogues of nicotine as novel antinociceptives.

Nicotinic ligands have been studied as novel therapeutic interventions in pain therapeutics since a long time. Several nicotinic agonists have been withdrawn from later stages of clinical trials due to lack of efficacy or narrow therapeutic window. These have been documented to act in the central nervous system and produce a wide range of pharmacological effects, including memory enhancing and analgesic actions, antianxiety, antidepressant and muscle coordination. Taking cognizance of the wide pharmacological profile of nicotine and its ligands, it was decided to evaluate some novel isoxazolidine analogues of nicotine for their potential as analgesics, using animal models like Eddy's hot plate and Tail immersion method. The compounds showed marked decrease in hyperalgesic response as compared to pentazocine at a wide range of doses. They were well tolerated as none of the compounds was found to have any seizure potential or mortality even at the highest doses. Thus, these compounds can be developed as potent antinociceptives with better safety profile than nicotine and other currently available pain therapeutics.

Unusual transformation of substituted-3-formylchromones to pyrimidine analogues: synthesis and antimicrobial activities of 5-(o-hydroxyaroyl)pyrimidines.

Substituted-3-formylchromones (4a-e) on reaction with 1,3-bis-dimethylaminomethylene-thiourea (5) in refluxing toluene solution give novel substituted 5-(o-hydroxyaroyl)pyrimidines (6a-e) in high yields. A mechanistic rationalization of the formation of products (6a-e) is proffered. Antimicrobial activities of all the synthesized compounds (6a-e) were evaluated against various fungal and bacterial strains. Compound 6d display significant antifungal activity (MIC 15) against Geotrichum candidum in comparison fluconazole used as positive control. Some of the compounds also display good antibacterial activity. Cytotoxic profile of compound 6d against HeLa cells indicates that at concentration (20 µM) no significant cell death (~2%) was observed.

Effect of Aegle marmelos (L.) Correa on alloxan induced early stage diabetic nephropathy in rats.

Diabetic nephropathy (DN) has a complex pathogenesis and poor prognosis due to the lack of therapeutic interventions. The present study investigates the effect of A. marmelos leaf extract (AME) on early alloxan induced DN. The treatment with AME was found to significantly decrease the fasting blood sugar, total cholesterol, blood urea, creatinine and renal TBARS and increased the levels of renal reduced glutathione and catalase significantly as compared to the diabetic control group. The maximum dose-dependent protection was observed at a dose of 200 mg kg(-1). Histological examination revealed marked reversal of the morphological derangements with AME treatment as indicated by a decrease in glomerular expansion, tubular dilatation and inflammatory cells. The present results conclude that AME treatment has a significant ameliorative effect on early changes induced in the kidneys by alloxan and improves the outcome of DN.

Possible involvement of PPAR-γ in the anticonvulsant effect of Aegle marmelos (L.) Correa.

Aegle marmelos is well documented for antihyperglycemic effect and PPAR-γ activation has been suggested to be the molecular mechanism of its action. Also, the plant has been used in Ayurveda as a brain tonic and has been postulated to have antidepressant activities. The present study was designed to investigate the anticonvulsant effects of A. marmelos leaf extract (AME) in pentylenetetrazole and maximal electroshock induced convulsions; involvement of PPAR-γ, nitric oxide pathway and effect of chronic AME treatment on post-ictal depression. AME was administered at doses of 50, 100 and 200 mg kg(-1) in PTZ and MES model. Severity of convulsions was noted in both the models. Pretreatment with bisphenol A diglycidyl ether (BADGE) was used to study the involvement of PPAR-γ and L-arginine and N-nitro-L-arginine methyl ester hydrochloride (L-NAME) to study the involvement of nitric oxide (NO). Chronic treatment with AME interspersed with sub maximal doses of PTZ (50 mg kg(-1)) on every fifth day up to 15 days was given to study post-ictal depression using forced swimming and actophotometer. AME showed significant increase in the onset time and decrease in the duration of convulsions in PTZ and MES models dose dependently. In MES a dose of 100 mg kg(-1) had effect comparable to phenytoin. Pretreatment with BADGE and L-arginine reversed the protective effect while L-NAME did not alter the protective effect, thereby indicating possible involvement of PPAR-γ and inhibition of NO. Chronic AME treatment ameliorated the post-seizure depression significantly as evidenced by increase in the locomotor activity and decrease in the immobility time.

Synthesis, conjugation and relaxation studies of gadolinium(III)-4-benzothiazol-2-yl-phenylamine as a potential brain specific MR contrast agent.

Magnetic resonance (MR) imaging is widely used in clinical research to map the structural and functional organization of the brain. We have designed and synthesized a Gd-based specific MR contrast agent that binds to regions in the brain. The presented compound {4-[(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]-7,10-bis-carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl} acetic acid (DO3A-BT) was synthesized by conjugating the chloroacetylated product of 4-benzothiazol-2-yl-phenylamine with a trisubstituted cyclen. The lanthanide complex (Ln-DO3A-BT) was evaluated in vitro for both MR (Gd-DO3A-BT) and optical (Eu-DO3A-BT) imaging applications. The complex Gd-DO3A-BT displays a relaxivity of r1 = 4.18 mM(-1) s(-1) at 4.7 T which is 1.2 times greater than Dotarem and significantly higher than the brain specific MR contrast agent Luxol Fast Blue (LFB). The protonation constant of the ligand (pKa1 = 9.91, pKa2 = 8.22, pKa3 = 5.01) and the stability constant of the complex formed between Gd(III), Eu(III) and Ca(II) and ligand DO3A-BT (log ßGdL = 18.4, log ßEuL = 18.3, log ßZn2L = 7.1, log ßCa2L = 6.3) were recorded by potentiometric titration. The constants reflect the high stability of the ligand with lanthanides compared with endogenous metal ions. The transmetalation stability of Gd-DO3A-BT toward Zn proved to be excellent with a rate constant of 3.07 × 10(-5) s(-1) which is in line with other tetraazatetraacetic acid (DOTA)-monoamide complexes. The hydration number (q) was found to be 0.92, and is calculated from the difference in the luminescence lifetime of Eu-DO3A-BT in H2O and D2O solutions to determine the coordination state of this complex. The in vivo biodistribution of (99m)Tc-DO3A-BT in BALB/c mice showed a brain uptake of 1.2% ID g(-1) at 2 min post injection when injected with mannitol which disrupts the blood-brain-barrier (BBB) due to osmotic shock. In vitro binding on the brain homogenate revealed a high uptake by the neuronal/glial cells for in vivo applications.

Pharmacognostic standardisation and antiproliferative activity of Aegle marmelos (L.) Correa leaves in various human cancer cell lines.

Therapeutic management of cancer is a great clinical challenge and alternative medicines are being extensively explored to have integrated approach to cure cancer. Aegle marmelos (L.) Correa (Rutaceae) is known for its hypoglycaemic, radioprotective, antidiarrhoeal and many other pharmacological activities. The present study is designed to carryout pharmacognostic standardisation and evaluation of antiproliferative activity of the leaf extracts Aegle marmelos (L.) Correa (Rutaceae) and the chromatographic fractions of the most active extract. Hexane, petroleum ether, chloroform and ethanol extracts of the shade dried leaves were prepared by soxhelation and antiproliferative activity was assessed using human cancer cell lines of lung (A-549), colon (CoLo-05), ovary (IGR-OV-1), prostrate (PC3), leukaemia (THP-1) and breast (MCF-7) cancer. Bioactivity-derived fractionation was carried out for most active extract by column chromatography. The phytochemical studies indicated alkaloids, anthraquinones, terpenoids in the alcohol, chloroform extracts and tannins, terpenoids, reducing sugars in the petroleum ether and hexane extracts. Ethanol extract showed maximum inhibition in colon and breast carcinoma cell lines at a dose of 100 µg/ml. Column chromatography of the ethanol extract yielded five fractions. Out of this, fractions 2, 4 and 5 showed significant inhibition in leukaemia cell line with IC50 of 12.5, 86.2 and >100 µg/ml for fractions 2, 4 and 5, respectively. High-performance thin layer chromatography of the fraction 2 revealed imperatorin as one of the major phytoconstituents. Among the different extracts investigated, ethanol extract exhibited significant antiproliferative activity and its fraction 2 containing furanocoumarin imperatorin showed antiproliferative activity against leukaemia cell line with IC50 of 12.5 µg/ml.

Anticonvulsant Activity of Schiff Bases of 3-Amino-6,8-dibromo-2-phenyl-quinazolin-4(3H)-ones.

Schiff bases (9a-l) of 3-amino-6,8-dibromo-2-phenyl-quinazolin-4-(3H)-ones (8) with various substituted aldehydes were obtained by refluxing 1:1 molar equivalents of the reactants in dry ethanol for 6 h. The aminoquinazoline (8) was inturn obtained from 3,5-dibromoantharlinic acid via intermediate (7). All the synthesized compounds (9a-l) were evaluated for their anticonvulsant activity on albino mice by maximal electroshock method using phenytoin as a standard. The compound (9l) bearing a cinnamyl function displays a very high activity (82.74 %) at dose level of 100 mg/kg b.w.

Pharmacognostic and antifungal investigations of Elaeocarpus ganitrus (Rudrakasha).

Rudrakasha is the dried bead obtained from the ripe fruit of Elaeocarpus ganitrus Roxb. (Family: Elaeocarpaceae). Microscopic studies revealed the presence of a hard endocarp with lignified isodiametric sclereids, seeds with membranous seed coat, which enclosed a dense cellular endosperm comprising of calcium oxalate druses. Physicochemical parameters showed that total ash was 1.36 times and 1.56 times more than the acid insoluble ash and water-soluble ash, respectively. Further, ethanol had a maximum extractable value of 2.4% and moisture content was found to be 9.7%. Different extracts, petroleum ether, chloroform, ethanol and water were prepared. Chemically the extracts showed the presence of phytosterols, fats, alkaloids, flavonoids, carbohydrates, proteins and tannins. The extracts were evaluated for antifungal activity on different fungal strains. Chlorofom and ethanol extracts have high antifungal activity against Candida albicans. Whereas, chloroform, ethanol and water extracts showed moderate inhibition against Aspergillus niger.

Cytotoxic activity of 3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromen-4-ones and 4-oxo-4H-chromene-3-carbothioic acid N-phenylamides.

6/6,7-Substituted-3-formylchromones (8a-g) were reacted with 2 equivalents thiobenzamide (9) in refluxing toluene to furnish substituted-3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromen-4-ones (10a-g) in high yields. Similarly, when substituted-2-anilino-3-formylchromones (8a-d) were reacted with thiobenzamide (9, 2 equivalents) in refluxing xylene, 4-oxo-4H-chromene-3-carbothioic acid N-phenylamides (11a-d) were obtained in high yields. All the compounds (10a-g) and (11a-d) display significant cytotoxic activity against a number of human cancer cell lines. Among these compounds 10e (IC(50) = 10 microM), 10b (IC(50) = 14.6 microM) and 10a (IC(50) = 10.5 microM) showed maximum cytotoxic activity on neuroblastoma. Also, the compound 10c (IC(50) = 10.5 microM) showed maximum cytotoxic activity on ovarian cancer cell line.

Synthesis and cytotoxic activity of some novel polycyclic gamma-butyrolactones.

Baeyer-Villiger oxidation of 5-aryl-7,11,11-trimethyltricyclo[5.4.0.0(3,6)]-undec-1-en-4-ones 4a-h by H(2)O(2) and formic acid in methanol yields mixtures of 3b,7,7-trimethyl-3-phenyl-3,3a,3b,4,5,6,7,8a-octahydro-1H-indeno-[1,2-c]furan-1-ones 8a-h and 3b,7,7-trimethyl-3-phenyl-3,3a,3b,4,5,6,7,8a-octahydro-1H-indeno-[1,2-c]furan-2-ones 9a-h in high yields. The obtained butyrolactones 8a-h display cytotoxic activity against a number of human cancer cells.

Synthesis of unsymmetrical substituted 1,4-dihydropyridines through thermal and microwave assisted [4+2] cycloadditions of 1-azadienes and allenic esters.

Thermal and microwave assisted [4+2] cycloadditions of 1,4-diaryl-1-aza-1,3-butadienes with allenic esters lead to cycloadducts, which after a 1,3-H shift afford variedly substituted unsymmetrical 2-alkyl-1,4-diaryl-3-ethoxycarbonyl-1,4-dihydropyridines in high yields. Reactions carried out under microwave irradiation are cleaner and give higher yields with much shortened reaction times. Density functional theory (DFT) at the B3LYP/6-31G* level has been used to calculate geometric features of the reactants, barrier for s-trans to s-cis and reverse isomerization of azadienes (5a-d, 10a-e), dihedral angles between N(1), C(2), C(3), and C(4) atoms of azadienes along with various indices such as chemical hardness (eta), chemical potential (micro), global electrophilicity (omega), and the difference in global electrophilicity (Deltaomega) between the reacting pairs and Fukui functions (f (+) and f(-)). The results revealed that s-trans is the predominant conformation of azadienes at ambient temperature and the barrier for conversion of the s-trans rotamer of 1-azadienes to s-cis may be the major factor influencing the chemoselectivity, i.e., [4+2] verses [2+2] cycloaddition. The regiochemistry of the observed cycloadditions is collated with the obtained local electrophilicity indices (Fukui functions). Transition states for the formation of both [4+2] and [2+2] cycloadducts as located at the PM3 level indicate that the transition state for the formation of [4+2] cycloadducts has lower energy, again supporting the earlier conclusion that preferred formation of [4+2] cycloaaducts at higher temperature may be a consequence of barrier for s-trans to s-cis transformation of 1-azadienes.

The effect of Allium sativum on ischemic preconditioning and ischemia reperfusion induced cardiac injury.

In the present study, the effect of garlic (Allium sativum) extract on ischemic preconditioning and ischemia-reperfusion induced cardiac injury has been studied. Hearts from adult albino rats of Wistar strain were isolated and immediately mounted on Langendorff's apparatus for retrograde perfusion. After 15 minutes of stabilization, the hearts were subjected to four episodes of 5 min ischemia, interspersed with 5 min reperfusion (to complete the protocol of ischemic preconditioning), 30 min global ischemia, followed by 120 min of reperfusion. In the control and treated groups, respective interventions were given instead of ischemic preconditioning. The magnitude of cardiac injury was quantified by measuring Lactate Dehydrogenase and creatine kinase concentration in the coronary effluent and myocardial infarct size by macroscopic volume method. Our study demonstrates that garlic extract exaggerates the cardio protection offered by ischemic preconditioning and per se treatment with garlic extract also protects the myocardium against ischemia reperfusion induced cardiac injury.

Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents.

6-Chloro-2-pyrrolidino-/morpholino-/piperidino-/N-methylpiperazino-3-formyl-chromones (13-16) and 6-fluoro-2,7-di-morpholino-/piperidino-/N-methylpiperazino-3-formylchromones (17-19) have been synthesized as potential topoisomerase inhibitor anticancer agents, and evaluated, in vitro, against Ehrlich ascites carcinoma (EAC) cells, and also in vivo on EAC bearing mice. The compounds displayed promising anticancer activity under these test systems and shall serve as useful 'leads' for further design.

Facile, regioselective [4 + 2] cycloaddition involving 1-aryl-4-phenyl-1-azadienes and allenic esters: an efficient route to novel substituted 1-aryl-4-phenyl-1,4-dihydropyridines.

[reaction: see text]1-Aryl-4-phenyl-1-azadienes undergo facile, regioselective [4 + 2] cycloaddition to the C2,C3 pi-bond of allenic esters in refluxing benzene, and the formed adducts undergo a 1,3-H shift to afford novel 2-alkyl-1-aryl-3-ethoxycarbonyl-4-phenyl-1,4-dihydropyridines (78-97%). However, when the reaction is carried at room temperature, besides the [4 + 2] addition, the [2 + 2] mode of addition involving C=N of azadiene and C3,C4 pi-bond of allenic esters also intervenes. The resulting N-aryl-2-ethoxy-carbonyl-methylidene-4-styrylazetidines (17-28%) undergo reorganization on silica gel to afford 2-cyclohexen-1-ones.