Namita Bansal

ETHAMBUTOL-SUGAR HYBRIDS AS POTENTIAL INHIBITORS OF MYCOBACTERIAL CELL-WALL BIOSYNTHESIS

Ethambutol is an established front-line agent for the treatment of tuberculosis, and is also active against Mycobacterium avium infection. However, this agent exhibits toxicity, and is considered to have low potency. The action of ethambutol on the mycobacterial cell wall, particularly the arabinan, and comparison of the structure of ethambutol with several of the cell-wall saccharides, suggested that ethambutol-saccharide hybrids might lead to agents with a more selective mechanism of action. To this end, eight ethambutol-saccharide hybrids were synthesized and screened against M. tuberculosis and several clinical isolates of M. avium.

Homologated aza analogs of arabinose as antimycobacterial agents

A series of hydrolytically-stable aza analogs of arabinofuranose was prepared and evaluated against Mycobacterium tuberculosis and M. avium. The compounds were designed to mimic the putative arabinose donor involved in biogenesis of the essential cell wall polysaccharide, arabinogalactan. Though most compounds displayed little activity in cell culture, one compound showed significant activity in infected macrophage models.

TIN(IV) CHLORIDE MEDIATED GLYCOSYLATION IN ARABINOFURANOSE, GALACTOFURANOSE AND RHAMNOPYRANOSE

Abstract Using tin(IV) chloride, O -glycosylation reactions were performed on peracylated D-arabinofuranose, d -galactofuranose and l -rhamnofuranose as well as 1-bromo- d -arabinofuranoses at room temperature in good anomeric purities and yields. In these circumstances, this coupling method has certain advantages over standard glycosylation reactions, such as the Koenigs-Knorr methods which use the 1-halosugar (synthesized from the 1-acyl derivative) and toxic mercury salts as the coupling agent.

The metabolism of 2-methyladenosine in Mycobacterium smegmatis

2-Methyladenosine (methyl-ado) has demonstrated selective activity against Mycobacterium tuberculosis, which indicates that differences in the substrate preferences between mycobacterial and human purine metabolic enzymes can be exploited to develop novel drugs for the treatment of mycobacterial diseases. Therefore, in an effort to better understand the reasons for the anti-mycobacterial activity of methyl-ado, its metabolism has been characterized in Mycobacterium smegmatis. In a wild-type strain, methyl-ado was phosphorylated by adenosine kinase to methyl-AMP, which was further converted to methyl-ATP and incorporated into RNA. In contrast, a mutant strain of M. smegmatis was isolated that was resistant to methyl-ado, deficient in adenosine kinase activity and was not able to generate methyl-ado metabolites in cells treated with methyl-ado. These results indicated that phosphorylated metabolites of methyl-ado were responsible for the cytotoxic activity of this compound. Methyl-ado was not a substrate for either adenosine deaminase or purine-nucleoside phosphorylase from M. smegmatis. Treatment of M. smegmatis with methyl-ado resulted in the inhibition of ATP synthesis, which indicated that a metabolite of methyl-ado inhibited one of the enzymes involved in de novo purine synthesis. These studies demonstrated the importance of adenosine kinase in the activation of methyl-ado to toxic metabolites in M. smegmatis.

Synthesis of a fluorescent arabinofuranosyl disaccharide: a probe for arabinosyltransferase activity in Mycobacterium tuberculosis

Abstract (5- N , N -Dimethylaminonaphthalene-1-sulfonamidoethyl)-5- O -(α- d -arabinofuranosyl)-α- d -arabinofuranoside 1 was synthesized as a fluorescent probe for the determination of arabinosyltransferase activity in Mycobacterium tuberculosis .

Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors.

Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.