Namrata Dwivedi

Mycobacterium tuberculosis NAD+-dependent DNA ligase is selectively inhibited by glycosylamines compared with human DNA ligase I

DNA ligases are important enzymes which catalyze the joining of nicks between adjacent bases of double-stranded DNA. NAD+-dependent DNA ligases (LigA) are essential in bacteria and are absent in humans. They have therefore been identified as novel, validated and attractive drug targets. Using virtual screening against an in-house database of compounds and our recently determined crystal structure of the NAD+ binding domain of the Mycobacterium tuberculosis LigA, we have identified N1, Nn-bis-(5-deoxy-α-d-xylofuranosylated) diamines as a novel class of inhibitors for this enzyme. Assays involving M.tuberculosis LigA, T4 ligase and human DNA ligase I show that these compounds specifically inhibit LigA from M.tuberculosis. In vitro kinetic and inhibition assays demonstrate that the compounds compete with NAD+ for binding and inhibit enzyme activity with IC50 values in the µM range. Docking studies rationalize the observed specificities and show that among several glycofuranosylated diamines, bis xylofuranosylated diamines with aminoalkyl and 1, 3-phenylene carbamoyl spacers mimic the binding modes of NAD+ with the enzyme. Assays involving LigA-deficient bacterial strains show that in vivo inhibition of ligase by the compounds causes the observed antibacterial activities. They also demonstrate that the compounds exhibit in vivo specificity for LigA over ATP-dependent ligase. This class of inhibitors holds out the promise of rational development of new anti-tubercular agents.

Current Status of Malaria Control

Malaria caused by Plasmodium parasites kills approximately 1-3 million people and causes disease in 300-500 million people annually throughout the world. The current approaches to curtail this disease include vector control, vaccination, immunotherapy and chemotherapy. The vector control is achieved by reducing vector density, interrupting their life cycle, and creating a barrier between the human host and mosquitoes. A number of vaccine candidates are being clinically tried and R&D effort in this direction is coming in a big way. Currently there are only limited safe drugs for the treatment of this disease, however, reports of emerging resistance against existing drugs warrant the introduction of new drugs, which are unlikely to come from pharmaceutical industries because of limited commercial opportunities. One of the most important current approaches to develop new drugs involves the synthesis of chemical libraries and evaluate them against most validated biochemical targets of malarial parasite. Although a number of such targets in antimalarial drug development are known today, yet only validated and selective biochemical targets including mitochondrial transport, glycolic pathway, folate pathway, proteases and heme metabolism, apicoplast metabolism, glycophospatidyl inositol, lipid metabolism (glycerophospholipids), peptidyl deformylase and oxidative stress in parasite-infected erythrocytes have been discussed here. The well known antimalarial drugs and different drug combinations for the treatment of malaria are also briefly reviewed. A survey of the recently discovered new molecules active against malaria has also been narrated. Lastly, the future of malaria chemotherapy and new directions emerging from literature has been elucidated.

Leishmania donovani pteridine reductase 1: Biochemical properties and structure-modeling studies

Pteridine reductase 1 (PTR1, EC 1.5.1.33) is a NADPH dependent short-chain reductase (SDR) responsible for the salvage of pterins in the protozoan parasite Leishmania. This enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Based on homology model drawn on recombinant pteridine reductase isolated from a clinical isolate of L. donovani, we carried out molecular modeling and docking studies with two compounds of dihydrofolate reductase specificity showing promising antileishmanial activity in vitro. Both the inhibitors appeared to fit well in the active pocket revealing the tight binding of the carboxylic acid ethyl ester group of pyridine moiety to pteridine reductase and identify the important interactions necessary to assist the structure based development of novel pteridine reductase inhibitors.

Recent Developments in Search of Antifilarial Agents

Filariasis, caused by spirunid nematodes, is one of the most prevalent diseases of tropical and subtropical countries and encompasses a number of different pathological conditions. It has great impact on the socioeconomic conditions of the people affected with this disease. The most common type of filariasis is a lymphatic filariasis caused by a parasite that lives in human lymph system. Like malaria, it is also caused by mosquito bites. The life cycle of the parasite, pathogenesis and diagnosis of filariasis have been briefly reviewed here in. Different strategies to control this disease have been discussed with major emphasis on the mechanisms, merits and demerits of the existing drugs and the drugs under pipeline. New antifilarial prototypes discovered recently and finally the future perspective to control the disease have also been elucidated.

Tetrabutylammonium Hydrogensulphate Catalyzed Efficient Synthesis of Glycosyl(aryl) Dihydropyrimidinones

An efficient synthesis of glycosyl dihydropyrimidinones using a three-component reaction of a βketo ester, glycosyl aldehyde, urea (or thiourea), in the presence of tetrabutylammonium hydrogensulphate and diethylene glycol as eco-friendly solvent has been reported. The reaction has been extended to the synthesis of aryl dihydropyrimidinones also. The glycosyl dihydropyrimidinones were obtained in excellent yields in less time than the methods already reported.

SYNTHESIS AND DNA TOPOISOMERASE-II INHIBITORY ACTIVITY OF UNNATURAL NUCLEOSIDES

The synthesis and biological activities of a number of unnatural nucleosides (23–43) is described. Nucleosides have been synthesized by SnCl4-catalyzed condensation of amino sugar acetates and silylated modified pyrimidines. Few of the 2′-O -acetyl derivatives of the nucleosides were hydrolyzed to the respective hydroxy derivatives by treatment with methanol saturated with ammonia. The compounds were screened against Filarial DNA-topoisomerase-II but only one of the compounds (29) inhibited this enzyme at 40 µg/mL of reaction mixture.