Namrata Dwivedi

Publications of Namrata Dwivedi

• Synthesis and optimization of antitubercular activities in a series of 4-(aryloxy)phenyl cyclopropyl methanols.

  Authors: Surendra S Bisht, Namrata Dwivedi, Vinita Chaturvedi, Namrata Anand, Mridul Misra, Rahul Sharma, Brijesh Kumar, Richa Dwivedi, Shyam Singh, Sudhir Kumar Sinha, Versha Gupta, P R Mishra, Anil K Dwivedi, Rama P Tripathi

  European journal of medicinal chemistry. 10/2010; 45(12):5965-78.

  A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4'-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanonesA series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4'-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones were further reduced to respective methanols. The antitubercular activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have shown minimum inhibitory concentration (MIC) of 3.12 μg/mL, while compounds 14, 25 and 18 have shown MIC of 1.56 μg/mL and 0.78 μg/mL respectively. One of the compounds, cyclopropyl-4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical isolates resistant strains with MIC 12.5 μg/mL. Compound 36 was orally active in vivo in mice against M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in lungs as compared to control on 30th day after infection.

• NAD(+)-dependent DNA ligase: a novel target waiting for the right inhibitor.

  Authors: Namrata Dwivedi, Divya Dube, Jyoti Pandey, Biswajit Singh, Vandna Kukshal, Ravishankar Ramachandran, Rama Pati Tripathi

  Medicinal research reviews. 08/2008; 28(4):545-68.

  DNA ligases (EC.6.5.1.1) are key enzymes that catalyze the formation of phosphodiester bonds at single stranded or double stranded breaks between adjacent 5' phosphoryl and 3' hydroxyl groups of DNA.DNA ligases (EC.6.5.1.1) are key enzymes that catalyze the formation of phosphodiester bonds at single stranded or double stranded breaks between adjacent 5' phosphoryl and 3' hydroxyl groups of DNA. These enzymes are important for survival because they are involved in major cellular processes like DNA replication/repair and recombination. DNA ligases can be classified into two groups on the basis of their cofactor specificities. NAD(+)-dependent DNA ligases are present in bacteria, some entomopox viruses and mimi virus while ATP-dependent DNA ligases are ubiquitous. The former have recently been drawing a lot of attention as novel targets for antibiotics to overcome current drug resistance issues. Currently a diverse range of inhibitors have been identified. There are several issues to be addressed in the quest for optimized inhibitors of the enzyme. In the first part of the review we summarize current structural work on these enzymes. Subsequently we describe the currently available classes of inhibitors. We also address modalities to improve the specificity and potencies of new inhibitors identified using protein structure based rational approaches. In conclusion, NAD(+)-dependent ligases show great promise and represent a novel drug target whose time has come.

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

  Authors: Pranav Kumar, Ashutosh Kumar, Shyam Sundar Verma, Namrata Dwivedi, Nasib Singh, Mohammad Imran Siddiqi, Rama Pati Tripathi, Anuradha Dube, Neeloo Singh

  Experimental parasitology. 07/2008;

  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 metabolicPteridine 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.

• Evaluation of Mycobacterium smegmatis as a possible surrogate screen for selecting molecules active against multi-drug resistant Mycobacterium tuberculosis.

  Authors: Vinita Chaturvedi, Namrata Dwivedi, Rama P Tripathi, Sudhir Sinha

  The Journal of general and applied microbiology. 12/2007; 53(6):333-7.

  New and better drugs are needed for tuberculosis (TB), particularly for the multi-drug resistant (MDR) disease. However, the highly infectious nature of MDR Mycobacterium tuberculosis restricts itsNew and better drugs are needed for tuberculosis (TB), particularly for the multi-drug resistant (MDR) disease. However, the highly infectious nature of MDR Mycobacterium tuberculosis restricts its use for large scale screening of probable drug candidates. We have evaluated the potential of a screen based on a 'fast grower' mycobacterium to shortlist compounds which could be active against MDR M. tuberculosis. Sensitivity profiles of M. smegmatis, M. phlei and M. fortuitum as well as MDR clinical isolates of M. tuberculosis were determined against anti-TB drugs isoniazid and rifampicin. Among the three fast growers, M. smegmatis was found to display a profile similar to MDR M. tuberculosis. Subsequently we evaluated the performance of M. smegmatis as a 'surrogate' screen for 120 compounds which were synthesized for anti-TB activity. Fifty of these molecules were active against M. tuberculosis H(37)Rv at a minimum inhibitory concentration (MIC) cutoff of <or=12.50 microg/ml. The M. smegmatis based screen showed 100% specificity and 78% sensitivity vis-à-vis MDR M. tuberculosis. These results highlight the utility of M. smegmatis as a primary screen to shortlist compounds for advanced screening against MDR M. tuberculosis.

• Diastereoselective synthesis of glycosylated prolines as alpha-glucosidase inhibitors and organocatalyst in asymmetric aldol reaction.

  Authors: Jyoti Pandey, Namrata Dwivedi, Nimisha Singh, A K Srivastava, A Tamarkar, R P Tripathi

  Bioorganic & medicinal chemistry letters. 04/2007; 17(5):1321-5.

  1,3-Dipolar cycloaddition of azomethine ylides and glycosyl E-olefins in presence of LDA led to diastereoselective formation of C-glycosylated proline esters. The selected esters on regioselective1,3-Dipolar cycloaddition of azomethine ylides and glycosyl E-olefins in presence of LDA led to diastereoselective formation of C-glycosylated proline esters. The selected esters on regioselective hydrolysis with LiOH gave C-glycosyl prolines. Few of the proline esters exhibited very good alpha-glucosidase inhibitory activity. The organocatalytic activity of the proline derivatives in a prototype Aldol reaction has also been investigated.

• Asymmetric organocatalysis with glycosyl-beta-amino acids: direct asymmetric aldol reaction of acetone with aldehydes.

  Authors: Namrata Dwivedi, Surendra S Bisht, Rama P Tripathi

  Carbohydrate research. 12/2006; 341(16):2737-43.

  Direct asymmetric aldol reaction of acetone with aromatic aldehydes was achieved in good yields and high enantioselectivity using 5-amino-5-deoxy-beta-L-ido-(alpha-D-gluco)-heptofuranuronic acids asDirect asymmetric aldol reaction of acetone with aromatic aldehydes was achieved in good yields and high enantioselectivity using 5-amino-5-deoxy-beta-L-ido-(alpha-D-gluco)-heptofuranuronic acids as a new class of organocatalysts.

• DBU assisted expeditious synthesis of glycosyl dienes via glycosylated beta-hydroxy esters.

  Authors: Shyam S Verma, Namrata Dwivedi, Biswajit K Singh, Rama P Tripathi

  Carbohydrate research. 09/2006; 341(11):1930-7.

  DBU catalyzed condensation of 3-O-benzyl(methyl)-5,6-dideoxy-1,2-O-isopropylidene-beta-L-threo-hept-4-enofuranuronates with different aldehydes produces the correspondingDBU catalyzed condensation of 3-O-benzyl(methyl)-5,6-dideoxy-1,2-O-isopropylidene-beta-L-threo-hept-4-enofuranuronates with different aldehydes produces the corresponding 3-O-benzyl(methyl)-6-carbethoxy-5,6-dideoxy-1,2-O-isopropylidene-7-phenyl-beta-L-threo-hept-4-enofuranoses. The latter on treatment with methanesulfonyl chloride followed by DBU catalyzed E2 reaction of the methanesulfonyloxy intermediates gave the respective 3-O-benzyl(methyl)-6-carbethoxy-5,6,7-trideoxy-1,2-O-isopropylidene-7-phenyl-beta-L-threo-hept-4,6-dienofuranose in moderate to good yields.

• Recent developments in search of antifilarial agents.

  Authors: Rama Pati Tripathi, Diksha Katiyar, Namrata Dwivedi, Biswajit K Singh, Jyoti Pandey

  Current medicinal chemistry. 02/2006; 13(27):3319-34.

  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 greatFilariasis, 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.

• An efficient synthesis of aryloxyphenyl cyclopropyl methanones: a new class of anti-mycobacterial agents.

  Authors: Namrata Dwivedi, Neetu Tewari, V K Tiwari, Vinita Chaturvedi, Y K Manju, A Srivastava, A Giakwad, S Sinha, R P Tripathi

  Bioorganic & medicinal chemistry letters. 11/2005; 15(20):4526-30.

  An efficient, high yield and one-pot synthesis of phenyl cyclopropyl methanones by reaction of different aryl alcohols with 4'-fluoro-4-chloro-butyrophenone in THF/DMF in the presence of NaH/TBAB isAn efficient, high yield and one-pot synthesis of phenyl cyclopropyl methanones by reaction of different aryl alcohols with 4'-fluoro-4-chloro-butyrophenone in THF/DMF in the presence of NaH/TBAB is reported. Most of the methanones were further reduced to respective alcohols or methylenes. All the compounds were evaluated for their anti-tubercular activities against M. tuberculosis H37Rv in vitro displaying MICs ranging from 25 to 3.125 microg/mL. The most active compounds showed activity against MDR strains and two of them (14 and 16) showed marginal enhancement of MST in mice.

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

  Authors: Sandeep Kumar Srivastava, Divya Dube, Neetu Tewari, Namrata Dwivedi, Rama Pati Tripathi, Ravishankar Ramachandran

  Nucleic acids research. 02/2005; 33(22):7090-101.

  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 inDNA 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, N(n)-bis-(5-deoxy-alpha-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 microM 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.

• Fighting tuberculosis: an old disease with new challenges.

  Authors: Rama P Tripathi, Neetu Tewari, Namrata Dwivedi, Vinod K Tiwari

  Medicinal research reviews. 02/2005; 25(1):93-131.

  Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. The mortality and spread of this disease has further been aggravated becauseTuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. The mortality and spread of this disease has further been aggravated because of synergy of this disease with HIV. A number of anti-TB drugs are ineffective against this disease because of development of resistance strains. Internationally efforts are being made to develop new anti-tubercular agents. A number of drug targets from cell wall biosynthesis, nucleic acid biosynthesis, and many other biosynthetic pathways are being unraveled throughout the world and are being utilized for drug development. In this review, socioeconomic problems in developing countries, efforts to control this disease in different individuals, the targets (known already and newly discovered), existing anti-tubercular agents including natural products and lead molecules, and the future prospects to develop new anti-TB agents are described.

• Synthesis and DNA topoisomerase-II inhibitory activity of unnatural nucleosides.

  Authors: Ram Chandra Mishra, Namrata Dwivedi, Pati Tripathi Rama, Iti Bansal, Jitendra Kumar Saxena

  Nucleosides, nucleotides & nucleic acids. 02/2005; 24(1):15-35.

  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 andThe 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 microg/mL of reaction mixture.

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

  Authors: Pranav Kumar, Ashutosh Kumar, Shyam Sundar Verma, Namrata Dwivedi, Nasib Singh, Mohammad Imran Siddiqi, Rama Pati Tripathi, Anuradha Dube, Neeloo Singh

  Experimental Parasitology.

  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 metabolicPteridine 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.