Prakas R. Maulik

Clotrimazole Inhibits Hemoperoxidase of Plasmodium falciparum and Induces Oxidative Stress PROPOSED ANTIMALARIAL MECHANISM OF CLOTRIMAZOLE

The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki= 2.85 μm, kinact = 0.9 min-1, and t½ = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5′-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.

A Convenient Synthesis and Hepatoprotective Activity of Imidazo(1,2-c)pyrimido(5,4-e)pyrimidine, Tetraazaacenaphthene and Tetraazaphenalene from Cyclic Ketene Aminals Through Tandem Addition-Cyclization Reactions {

A novel one-pot synthesis of imidazo[1,2-c]pyrimido[5,4-e]pyrimidinones (2), tetraazaacenaphthene-3,6-diones (4), tetarazaphenalene-1,7-dione (4d) is delineated from the reaction of cyclic ketene aminal (1) and alkyl or aryl isothiocyanate through tandem addition-cyclization reactions. However, reaction of ketene aminal (1a) with alkyl isothiocyanate only yielded angularly cyclized product 5 which did not react further to yield 6. The structure of 2c and 4d was ascertained by single crystal X-ray diffraction analysis which demonstrated a network of various inter- and intramolecular interactions, responsible for the stability and packing of the molecules in the crystalline state. Some of the compounds (2a--h) were screened for hepatoprotective activity but only 2a was found most effective.

1H NMR and X-ray crystallographic analysis of 1,2-bis(4,6-diethylthio-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethane and its ‘propylene linker’-analog: molecular recognition versus crystal engineering ☆

Abstract Proton NMR analysis on newly synthesized 1,2-bis(4,6-diethylthio-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethane, 2c , and 1,2-bis(4,6-diethylthio-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane, 2d , showed intramolecular stacking in solution. X-Ray crystallography on 2c and 2d , however, confirmed the presence of such intramolecular stacking only in case of the ‘propylene linker’ compound, 2d , while the ‘ethylene linker’ compound, 2c , was devoid of it.

Significant rate accelerated synthesis of glycosyl azides and glycosyl 1,2,3-triazole conjugates

AbstractAn efficient and significantly rapid access of a series of glycosyl azides and glycosyl 1,2,3-triazole conjugates is reported using modified one-pot reaction conditions. In both cases yields were excellent and single diastereomers were obtained. FigureRapid preparation of 4-substituted glycosyl 1,2,3-triazole conjugates from glycosyl bromides.

Cytotoxic cycloartane triterpene and rare isomeric bisclerodane diterpenes from the leaves of Polyalthia longifolia var. pendula.

A 24-methylenecycloartane-3 β, 16 β, 23 β-triol, Longitriol (1), rare bisclerodane imides, Longimide A (2) and previously known Longimide B (3) were isolated from ethanolic extract of the leaves of Polyalthia longifolia var. pendula. This is the first example of isolation of any cycloartane triterpene from this plant source. Structures were determined by extensive (1D and 2D NMR) spectroscopic data analysis combined with ESI MS/MS fragmentation and X-ray analysis. Furthermore, Compounds 1 and 2 were evaluated for their cytotoxic effects against four human cancer cell lines and found to be most active against cervical carcinoma cell lines with IC(50) value of 10.03 and 4.12 μg/mL, respectively.

An expeditious synthesis of imidazo[1,2-a]pyridines through nucleophile induced ring transformation reactions of 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carbonitriles

An efficient and convenient synthesis of 2-(5-aryl-8-nitro-2,3-dihydroimidazo[1,2-a]pyridin-7(1H)-ylidene)acetonitriles (3) and 6-aryl-4-{2-[(E)-nitromethylidene]-1-imidazolidinyl}-2-oxo-2H-pyran-3-carbonitriles (4) through nucleophile induced ring transformation of suitably functionalized 2H-pyran-2-one (1) from imidazoliden-2-ylidene nitromethane is delineated.

Carbanion induced synthesis of annulated unsymmetrical biaryls through ring transformation of 2H-pyran-2-oneCentral Drug Research Institute communication no. 6207

An innovative and convenient one-pot synthesis of unsymmetrical macrocyclic biaryls (3, 5 and 8), dibenzo[a,c]cycloheptenes (10), 3,4-dihydro-2(1H)-naphthones (15), tetrahydroisoquinolines (18), dihydro-1H-isothiochromenes (20), benzo[c]thiochromenes (22) and 2,3-dihydro-1-benzothiophenes (24) is described. These compounds are obtained through base-catalyzed ring transformation reactions of suitably functionalized 2H-pyran-2-ones (1,6) by a carbanion, generated from cycloalkanone (2,4,7), benzosuberone (9), cyclohexanedione monoketal (12), 4-piperidone (17), tetrahydrothiopyran-4-one (19), thiochroman-4-one (21) or tetrahydrothiophene-3-one (23).

Bile acid-based 1,2,4-trioxanes: synthesis and antimalarial assessment.

A new series of bile acid-based trioxanes 23a-d, 24a-d, 25a-d, 26a, 26b, and 26d have been synthesized and assessed for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. The antimalarial activity of these trioxanes showed a strong dependence on the side-chain length; shortening side-chain length lead to increase in activity. The antimalarial activity also showed even stronger dependence on the stereochemistry at C3 and C6 (C21 in Figure 5) of the trioxane moiety. Of the two diastereomers isolated of each of the trioxanes, more polar one was significantly more active than the less polar one. The more polar diastereomer of the trioxanes 26a, 26b, and 26d, were the most active compounds of the series. All these three trioxanes provided 100% protection at 24 mg/kg×4 days. In this model β-arteether provided 100% and 20% protection at 48 mg/kg×4 days and 24 mg/kg×4 days, respectively.

Concise chemical synthesis of a tetrasaccharide repeating unit of the O-antigen of Hafnia alvei 10457

AbstractConcise chemical synthesis of a tetrasaccharide repeating unit of the O-antigen of Hafnia alvei 10457 is reported. Construction of the tetrasaccharide as its 4-methoxyphenyl glycoside was achieved by condensation of less abundant monosaccharide units such as, d-galactofuranose, N-acetyl-d-galactosamine and N-acetylneuraminic acid. The synthetic strategy consists of the preparation of suitably protected required monosaccharide intermediates from the commercially available reducing sugars and high yielding glycosylation reactions. Graphical abstractA concise synthesis of a tetrasaccharide repeating unit of the O-antigen of Hafnia alvei 10457 is reported. The synthetic strategy consists of the preparation of suitably protected required monosaccharide intermediates from the commercially available reducing sugars and high yielding glycosylation reactions.

Novel diastereoselective synthesis of spiropyrrolidine-oxindole derivatives as anti-breast cancer agents

A novel class of diastereoselective spiropyrrolidine-oxindole derivatives were synthesized from isatin, 2-phenylthiazolidine-4-carboxylic acid and chalcone in a one-pot multicomponent reaction via 1,3-dipolar cycloaddition. The advantages of this methodology are the mild reaction conditions, high diastereoselectivity and high yield. These derivatives exhibited promising anti-cancer activity against the human breast cancer cell lines.