Rama Pati Tripathi

Organocatalyzed highly atom economic one pot synthesis of tetrahydropyridines as antimalarials

A highly atom economic one pot synthesis of tetrahydropyridines was achieved by L-proline/TFA catalysed multicomponent reaction of beta-keto-esters, aromatic aldehydes and anilines. The synthesized compounds were screened against Plasmodium falciparum in vitro and one of them showed antimalarial activity with MIC as low as 0.09 microg/mL.

NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors.

DNA ligases utilize either ATP or NAD+ as cofactors to catalyze the formation of phosphodiester bonds in nicked DNA. Those utilizing NAD+ are attractive drug targets because of the unique cofactor requirement for ligase activity. We report here the crystal structure of the adenylation domain of the Mycobacterium tuberculosis NAD+-dependent ligase with bound AMP. The adenosine nucleoside moiety of AMP adopts a syn-conformation. The structure also captures a new spatial disposition between the two subdomains of the adenylation domain. Based on the crystal structure and an in-house compound library, we have identified a novel class of inhibitors for the enzyme using in silico docking calculations. The glycosyl ureide-based inhibitors were able to distinguish between NAD+- and ATP-dependent ligases as evidenced by in vitro assays using T4 ligase and human DNA ligase I. Moreover, assays involving an Escherichia coli strain harboring a temperature-sensitive ligase mutant and a ligase-deficient Salmonella typhimurium strain suggested that the bactericidal activity of the inhibitors is due to inhibition of the essential ligase enzyme. The results can be used as the basis for rational design of novel antibacterial agents.

Synthesis and antitubercular screening of imidazole derivatives

A series of imidazole based compounds were synthesized by reacting simple imidazoles with alkyl halides or alkyl halocarboxylate in presence of tetrabutylammonium bromide (TBAB). The compounds bearing carbethoxy group undergo amidation with different amines in the presence of DBU to give respective carboxamides. The synthesized compounds were screened against Mycobacterium tuberculosis where compound 17 exhibited very good in vitro antitubercular activity and may serve as a lead for further optimization.

Application of Huisgen (3 + 2) cycloaddition reaction: Synthesis of 1-(2,3-dihydrobenzofuran-2-yl-methyl [1,2,3]-triazoles and their antitubercular evaluations

1,4-Disubstituted-1,2,3-triazoles (3-27) have been synthesized by [3+2] cycloaddition of different 2-(azidomethyl)-dihydronaptho(benzo)furans (2a, 2b, 2c and 2d) with different alkynes. All the compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv. Compounds 2a, 7, 9, 12 and 14 exhibited antitubercular activities with MIC ranging from 12.5 to 3.12 microg/ml.

Preparation and reactions of sugar azides with alkynes: synthesis of sugar triazoles as antitubercular agents

5-azido-5-deoxy-xylo-, ribo-, and arabinofuranoses were prepared by the reaction of the respective 5-O-(methanesulfonyl) or p-toluenesulfonyl derivatives with NaN3 in DMF. The intermediate 5-azido-5-deoxy glycofuranoses on 1,3-cycloaddition with different alkynes in the presence of CuSO4 and sodium ascorbate gave the corresponding sugar triazoles in very good yields. The synthesized sugar triazoles were evaluated for their antitubercular activity against Mycobacterium tuberculosis H37Rv, where one of the compounds displayed mild antitubercular activity in vitro with MIC 12.5 microg/mL.

Synthesis of glycosylated β-amino acids as new class of antitubercular agents

Abstract A series of glycosylated β-amino acids was prepared and evaluated against Mycobacterium tuberculosis, M. avium, M. fortuitum and M. smegmatis. The compounds were designed to mimic the enzyme d -alanine racemase and glycosyl transferase involved in the biosynthesis of essential cell wall peptidoglycan and arabinogalactan. Though most of the compounds exhibited little activity, however, one showed significant activity against all the strains in cell culture and activity was confirmed by B actec method.

Carbohydrate based Potential Chemotherapeutic Agents: Recent Developments and their Scope in Future Drug Discovery

In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.

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.

Application of click chemistry towards an efficient synthesis of 1,2,3-1H-triazolyl glycohybrids as enzyme inhibitors

An efficient synthesis of novel 1,2,3-1H-triazolyl glycohybrids with two or more than two sugar units or a chromenone moiety via copper-catalysed azide-alkyne cycloaddition (CuAAC), a 1,3-dipolar cycloaddition of glycosyl azides to 2,3-unsaturated alkynyl glycosides or propargyloxy coumarins is described. The synthesised glycohybrids were screened for their α-glucosidase, glycogen phosphorylase and glucose-6-phosphatase inhibitory activities. A few of the glycohybrids showed promising inhibitory activities against these enzymes.

Synthesis of 2-sulfanyl-6-methyl-1,4-dihydropyrimidines as a new class of antifilarial agents.

A series of 2-sulfanyl-6-methyl-1,4-dihydropyrimidines (8-21) were synthesized in good yields by alkylation of 5-methyl-6-phenyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid ethyl esters (2-7) with different alkyl or aralkyl halides in the presence of a combination of anhydrous K(2)CO(3) and catalytic amount of tetrabutyl ammonium bromide. The title compounds were evaluated for their antifilarial activity against adult parasites of human lymphatic filarial parasite Brugia malayi (sub-periodic strain) in vitro and in vivo at various concentrations. One of the compounds (18) showed promising antifilarial activity.