Prashant Singh

Publications of Prashant Singh

• In silico screening, structure-activity relationship, and biologic evaluation of selective pteridine reductase inhibitors targeting visceral leishmaniasis.

  Authors: Jaspreet Kaur, Pranav Kumar, Sargam Tyagi, Richa Pathak, Sanjay Batra, Prashant Singh, Neeloo Singh

  Antimicrobial agents and chemotherapy. 02/2011; 55(2):659-66.

  In this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1In this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1 (PTR1) in Leishmania parasites. Twelve compounds afforded from Baylis-Hillman chemistry were docked by using the QUANTUM program into the active site of Leishmania donovani PTR1 homology model. The biological activity for these compounds was estimated in green fluorescent protein-transfected L. donovani promastigotes, and the most potential analogue was further investigated in intracellular amastigotes. Structure-activity relationship based on homology model drawn on our recombinant enzyme was substantiated by recombinant enzyme inhibition assay and growth of the cell culture. Flow cytometry results indicated that 7-(4-chlorobenzyl)-3-methyl-4-(4-trifluoromethyl-phenyl)-3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one (compound 7) was 10 times more active on L. donovani amastigotes (50% inhibitory concentration [IC(50)] = 3 μM) than on promastigotes (IC(50) = 29 μM). Compound 7 exhibited a K(i) value of 0.72 μM in a recombinant enzyme inhibition assay. We discovered that novel pyrimido[1,2-a]pyrimidin-2-one systems generated from the allyl amines afforded from the Baylis-Hillman acetates could have potential as a valuable pharmacological tool against the neglected disease visceral leishmaniasis.

• Leishmania donovani: oral therapy with glycosyl 1,4-dihydropyridine analogue showing apoptosis like phenotypes targeting pteridine reductase 1 in intracellular amastigotes.

  Authors: Jaspreet Kaur, Nasib Singh, Biswajit Kumar Singh, Anuradha Dube, Rama Pati Tripathi, Prashant Singh, Neeloo Singh

  Experimental parasitology. 02/2010; 125(3):310-4.

  Glycosyl 1,4-dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-beta-l-threo pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) synthesizedGlycosyl 1,4-dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-beta-l-threo pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) synthesized in our laboratory, inhibited Leishmania donovani infection in vitro and in hamsters (Mesocricetus auratus) when administered orally. This analogue is nontoxic, cell-permeable and orally effective. This glycosyl dihydropyridine analogue functioned through arrest of cells in sub-G0/G1-phase, triggering mitochondrial membrane depolarization-mediated programmed cell death of the intracellular amastigotes.

• Leishmania donovani: A glycosyl dihydropyridine analogue induces apoptosis like cell death via targeting pteridine reductase 1 in promastigotes.

  Authors: Jaspreet Kaur, Biswajit Kumar Singh, Rama Pati Tripathi, Prashant Singh, Neeloo Singh

  Experimental parasitology. 08/2009;

  Targeting of pteridine reductase1 (PTR1) in Leishmania is essential for development of successful antifolate chemotherapy. In search for specific inhibitors of PTR1 we have previously reported phenylTargeting of pteridine reductase1 (PTR1) in Leishmania is essential for development of successful antifolate chemotherapy. In search for specific inhibitors of PTR1 we have previously reported phenyl 1, 4-dihydropyridine ring as the lead structure showing antileishmanial efficacy in vitro and by the oral route in vivo. In this study we present programmed cell death inducing potential of this glycosyl dihydropyridine analogue (2, 6-dimethyl-4-(3-O-benzyl-1, 2-O-isopropylidene-beta-L-threo-pentofuranos-4-yl)-1-phenyl-1, 4-dihydro-pyridine-3, 5-dicarboxylic acid diethyl ester). Flow cytometric analysis revealed that this analogue induces cell cycle arrest at G2/M phase with subsequent increase in sub-G1 peak. Incubation of Leishmania promastigotes with this analogue causes exposure of phosphatidylserine to the outer leaflet of plasma membrane, formation of reactive oxygen species, depolarization of mitochondrial membrane potential and concomitant nuclear alterations that included DNA fragmentation. The results from this study on promastigotes give important lead to investigate further in intracellular amastigotes, the biologically relevant parasite stage in host macrophages.

• Efficient Parameter Extraction for 3-D Structures in Layered Dielectric Media

  Authors: Sharad Kapur, David E. Long, Prashant Singh

  Microwave Conference, 1997. 27th European; 10/1997

  Boundary element methods (BEM) are often used to extract models of integrated circuit structures. BEM extraction, however, involves solving a dense system of linear equations, and using directBoundary element methods (BEM) are often used to extract models of integrated circuit structures. BEM extraction, however, involves solving a dense system of linear equations, and using direct factorization methods can be prohibitive for large problems. In this paper we describe a novel algorithm for efficient parameter extraction of conductors embedded in multi-layered dielectric media. A Green's function, which accounts for the variation in the layered dielectric media, is constructed from image theory [8]. We then use an SVD-accelerated Method of Moments (MoM) solver [2] for the solution of the associated dense matrix. Results are presented to show that the method is accurate and can be two orders of magnitude faster than Gaussian elimination and one order of magnitude faster than standard iterative schemes. The algorithm is used for the extraction of parasitics for an RF IC test socket. The extracted equivalent circuit model is compared to measurements and found to agree within 3 dB.

• Leishmania donovani: A glycosyl dihydropyridine analogue induces apoptosis like cell death via targeting pteridine reductase 1 in promastigotes

  Authors: Jaspreet Kaur, Biswajit Kumar Singh, Rama Pati Tripathi, Prashant Singh, Neeloo Singh

  Experimental Parasitology.

  Targeting of pteridine reductase 1 (PTR1) in Leishmania is essential for development of successful antifolate chemotherapy. In search for specific inhibitors of PTR1 we have previously reportedTargeting of pteridine reductase 1 (PTR1) in Leishmania is essential for development of successful antifolate chemotherapy. In search for specific inhibitors of PTR1 we have previously reported phenyl 1,4-dihydropyridine ring as the lead structure showing antileishmanial efficacy in vitro and by the oral route in vivo. In this study, we present programmed cell death inducing potential of this glycosyl dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-β-l-threo-pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester). Flow cytometric analysis revealed that this analogue induces cell cycle arrest at G2/M phase with subsequent increase in sub-G1 peak. Incubation of Leishmania promastigotes with this analogue causes exposure of phosphatidylserine to the outer leaflet of plasma membrane, formation of reactive oxygen species, depolarization of mitochondrial membrane potential and concomitant nuclear alterations that included DNA fragmentation. The results from this study on promastigotes give important lead to investigate further in intracellular amastigotes, the biologically relevant parasite stage in host macrophages.

• Leishmania donovani: Oral therapy with glycosyl 1,4-dihydropyridine analogue showing apoptosis like phenotypes targeting pteridine reductase 1 in intracellular amastigotes

  Authors: Jaspreet Kaur, Nasib Singh, Biswajit Kumar Singh, Anuradha Dube, Rama Pati Tripathi, Prashant Singh, Neeloo Singh

  Experimental Parasitology.

  Glycosyl 1,4-dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-β-l-threo pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) synthesized inGlycosyl 1,4-dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-β-l-threo pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) synthesized in our laboratory, inhibited Leishmania donovani infection in vitro and in hamsters (Mesocricetus auratus) when administered orally. This analogue is nontoxic, cell-permeable and orally effective. This glycosyl dihydropyridine analogue functioned through arrest of cells in sub-G0/G1-phase, triggering mitochondrial membrane depolarization-mediated programmed cell death of the intracellular amastigotes.