Rumana Ahmad

Synthesis and bioevaluation of glycosyl ureas as α-glucosidase inhibitors and their effect on mycobacterium

Glycosyl amino esters (2-13) on reaction with different isocyanates resulted in quantitative conversion to glycosyl ureas (14--32). Few of the selected ureas (15-20, 22-28, 30 and 32) on cyclative amidation with DBU/TBAB/4 A MS gave respective dihydropyrimidinones in fair to good yields (33-47). The compounds were screened for alpha-glucosidase inhibitory activity and two (19 and 23) of them showed strong inhibition against rat intestinal alpha-glucosidase. The compounds were also screened against Mycobacterium aurum, however, only one (19) of them exhibited marginal antitubercular activity.

DBU-Assisted Cyclorelease Elimination: Combinatorial Synthesis and γ- Glutamyl Cysteine Synthetase and Glutathione-S-Transeferase Modulatory Effect of C-Nucleoside Analogs

A combinatorial library of 60C- nucleoside analogs was synthesized by sequential coupling of building blocks followed by cyclative cleavage with DBU in an efficient manner. Only DMSO soluble compounds were tested for their modulatory effect against filarial gamma-glutamyl cysteine synthetase (gamma-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial gamma-GCase, whereas, most of them stimulated filarial GSTs.

Biochemical composition and metabolic pathways of filarial worms Setaria cervi: search for new antifilarial agents.

The main problem regarding the chemotherapy of filariasis is that no safe and effective drug is available yet to combat the adult human filarial worms. Setaria cervi, the causal organism of setariasis and lumbar paralysis in cattle, is routinely employed as a model organism for conducting biochemical and enzymatic studies on filarial parasites. In view of the practical difficulties in procuring human strains of Wuchereria bancrofti and Brugia malayi for drug screening, the bovine filarial parasite S. cervi, resembling the human species in having microfilarial periodicity and chemotherapeutic response to known antifilarial agents, is widely used as a model in such studies. For a rational approach to antifilarial chemotherapy, knowledge of the biochemical composition and metabolic pathways of this helminth parasite may be of paramount importance, so that more potent antifilarial agents based on specific drug targets can be identified in drug discovery programmes. The present review provides an update on the biochemistry of the important metabolic pathways functioning within this potentially important bovine parasite, that have so far been studied, and on those that need to be investigated further so as to identify novel drug targets that can be exploited for designing new antifilarial drugs.

Purification and biochemical characterization of cytosolic glutathione-S-transferase from filarial worms Setaria cervi.

The present study reports the purification and characterization of GST from cytosolic fraction of Setaria cervi. GST activity was determined in various subcellular fractions of bovine filarial worms S. cervi (Bubalus bubalis Linn.) and was found to be localized mainly in the cytosolic and microsomal fractions. The soluble enzyme from S. cervi was purified to homogeneity using a combination of salt precipitation, centrifugation, cation exchange and GSH-Sepharose affinity chromatography followed by ultrafiltration. SDS-PAGE analysis revealed a single band and activity staining was also detected on PAGE gels. Gel filtration and MALDI-TOF studies revealed that the native enzyme is a homodimer with a subunit molecular mass of 24.6 kDa. Comparison of kinetic properties of the parasitic and mammalian enzymes revealed significant differences between them. The substrate specificity and inhibitor profile of cytosolic GST from S. cervi appeared to be different from GST from mammalian sources.

Inhibition of glutathione-S-transferase from Plasmodium yoelii by protoporphyrin IX, cibacron blue and menadione: implications and therapeutic benefits

The rapidly developing resistance to drugs used for prophylaxis and treatment of malaria makes the identification of novel drug targets necessary. Glutathione-S-transferase (GST, E.C. 2.5.1.18), an important enzyme of the glutathione (GSH) cycle, is considered to be an essential detoxification enzyme in malarial parasites. Selective inhibition of this enzyme from malarial parasites by various classes of inhibitors may be viewed as a potential chemotherapeutic strategy to combat malaria. Purified GST from Plasmodium yoelii was inhibited by compounds like protoporphyrin IX, cibacron blue, as well as by the GSH depletor menadione. Cytosolic GST was inhibited to varying degrees by each compound. A characteristic inhibitor constant (Ki) was obtained for each inhibitor. The possible consequences of selective inhibition of parasitic GST to that of the host are discussed in relation to the chemotherapy of malaria.

Synthesis of α-Mannosylated Phenolics as α-Glucosidase Inhibitors*

BF3OEt2-catalysed glycosidation of phenolic compounds 3 and 6 with the mannofuranosyl glycosyl donor 2 separately gave the corresponding α-mannofuranosyl derivatives 4 and 7 in good yield, and the latter on selective deacetonation (hydrolysis) with 2% aqueous HCl afforded 5 and 8 respectively. Compounds 4 and 7 inhibited rat intestinal α-glucosidase more effectively than a standard drug acarbose.

Synthesis and biological evaluation of potential modulators of malarial glutathione-S-transferase(s)

Glutathione-S-transferase(s) (E.C.2.5.1.18, GSTs) have been investigated in parasitic protozoans with respect to their biochemistry and they have been identified as potential vaccine candidates in protozoan parasites and as a target in the synthesis of new antiparasitic agents. In a search towards the identification of novel biochemical targets for antimalarial drug design, the area of Plasmodium glutathione metabolism provides a number of promising chemotherapeutic targets. GST activity was determined in various subcellular fractions of malarial parasites Plasmodium yoelii and was found to be localized mainly in the cytosolic fraction (specific activity, c. 0.058 ± 0.016 μmol/min/mg protein). Hemin, a known inhibitor of mammalian GST(s), maximally inhibited this enzyme from P. yoelii to nearly 86%. In a search towards synthetic modulators of malarial GST(s), 575 compounds belonging to various chemical classes were screened for their effect on crude GST from P. yoelii and 92 compounds belonging to various chemical classes were studied on recombinant GST from P. falciparum. Among all the compounds screened, 83 compounds inhibited/stimulated the enzyme from P. yoelii/P. falciparum to the extent of 40% or more.

MODULATION OF FILARIAL GLUTATHIONE-S-TRANSFERASE(S) ACTIVITY: A POSSIBILITY TOWARDS THE SYNTHESIS OF NEW CLASSES OF ANTIFILARIAL AGENTS

In a search towards the inhibitors/stimulators of filarial glutathione-S-transferase(s) (GST(s)), the major detoxification enzymes, a total of 335 compounds belonging to three major chemical classes were looked for their effect on soluble filarial GST(s). Among a total of 10 diglycosylated diaminoalkanes (DGDA), 4 showed more than 50% stimulatory effect, among 10 glycosylated hydroxamic acids, 2 showed more than 50% stimulatory effect and among 4 glycopeptides, 3 showed more than 50% stimulatory effect. Among a total of 38 glycosyl ureas, 2 showed more than 50% inhibitory effect. Among a total of 66 glycosyl ureas/ thioureas and glycopeptidyl ureas, 3 showed more than 50% stimulatory effect whereas 2 showed more than 50% inhibitory effect. Among a total of 59 C-nucleosides/ S-containing nucleosides, 24 showed more than 50% stimulatory effect.

CYTOSOLIC AND MICROSOMAL GLUTATHIONE-S-TRANSFERASES FROM BOVINE FILARIAL WORMS SETARIA CERVI

The work presented here deals with the status of glutathione-S-transferase (GST; E.C. 2.5.1.18), the major enzyme of the phase II detoxification pathway, in bovine filarial worms Setaria cervi. GST activity was determined in various subcellular fractions of bovine filarial worms S. cervi (Bubalus bubalis Linn.) and was found to be mainly associated with cytosolic and microsomal fractions. The respective specific activities of the enzyme from cytosolic and microsomal fractions of S. cervi females were determined to be 0.122 ± 0.024 and 0.010 ± 0.0052 μmol/min/mg protein, respectively. Cytosolic enzyme was found to possess optimal activity between pH 6.5 and 7.5, whereas the microsomal enzyme showed a broad pH optima, centered at pH 6.0. Kinetic studies on the cytosolic and microsomal forms of the enzyme revealed significant differences between them, thereby indicating that microsomal GST from S. cervi is quite distinct to the cytosolic protein catalyzing the same reaction.

Neurocysticercosis: a review on status in India, management, and current therapeutic interventions

Tapeworms (cestodes) are segmented flatworms responsible for causing diseases that may prove fatal and difficult to treat in the absence of proper treatment and efficient drugs. Neurocysticercosis (NCC) is a common parasitic infection of the central nervous system and a major contributor to epilepsy caused by the metacestode (larva) of the human tapeworm Taenia solium, characterized by a range of pathological symptoms including epileptic seizures, headaches, and hydrocephalus. Cysticercosis is considered as a “biological imprint” of the socioeconomic development of a community in general and a country in particular. It is the single most common cause of epilepsy in the resource-poor endemic regions of the world, including most of South and Central America, India, Southeast Asia, China, and sub-Saharan Africa. A vast degree of variation in the neuropathology and clinical symptoms of NCC often makes it difficult to diagnose and manage. To add to it, emerging drug resistance to known anti-parasitic agents, together with the inability of these agents to prevent re-infection and relapse, further complicates the disease scenario. The aim of the current review was to provide the latest update on NCC with special emphasis on the Indian scenario, along with current and novel methods of diagnosis as well as scope of development for novel detection techniques, novel targets for drug development, and therapeutic interventions, as well as future challenges.