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 N(1), N(n)-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 IC(50) 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

New ways to treat tuberculosis using dendrimers as nanocarriers

International audienceTuberculosis (TB) is a contagious infection that usually attacks not only the lungs, but also brain and spine. More than twenty drugs have been developed for the treatment of TB, but most of them were developed some years ago. They are used in different combinations. Isoniazid and Rifampicin are examples of the five first line TB drugs, whereas, for instance, Levofloxacin, Kanamycin and Linezolid belong to the second line drugs that are used for the treatment of drug resistant TB. Several new bicyclic nitroimidazoles (e.g., Delamanid) without mutagenic effects were developed. New TB drugs need to provide several main issues such as more effective, less toxic, and less expensive for drug resistant TB. Besides polymeric, metal-based nanoparticles, polymeric micelles and polymers, dendrimer nanostructures represent ideal delivery vehicles and offer high hopes for the future of nanomedicine. In this original review, we present and analyze the development of anti-TB drugs in combination with dendrimers. Few articles have highlighted the encapsulation of anti-TB drugs with dendrimers. Due to their unique structure, dendrimers represent attractive candidates for the encapsulation and conjugation of other anti-TB drugs presenting important drawbacks (e.g., solubility, toxicity, low bioavailability) that hinder their development, including clinic trials

One-Pot Copper(I)-Catalyzed Ligand/Base-Free Tandem Cyclooxidative Synthesis of Quinazolinones

A novel and efficient Cu­(I)-catalyzed ligand- and base-free multipathway domino strategy has been developed for the synthesis of 2-substituted quinazolinones. The reaction utilizes 2-bromobenzamide and multiform substrates such as aldehydes, alcohols, and methyl arenes for a one-pot protocol, whereas TMSN₃ is used as a nitrogen source. A wide range of substrate scope, functional group tolerance, and operational simplicity are synthetically useful features

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

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 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 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

A Strategy for the Synthesis of Anthraquinone-Based Aryl‑<i>C</i>‑glycosides

An efficient and simple strategy for the synthesis of a diverse range of anthraquinone-based aryl-<i>C</i>-glycosides has been developed. It involves the sequential Diels–Alder reaction and oxidative aromatization with the preformed glycosyl diene and dienophiles. The glycosyl dienes were obtained from simple sugars by tandem one-pot substitution and elimination reaction

Safe Polycationic Dendrimers as Potent Oral In Vivo Inhibitors of Mycobacterium tuberculosis : A New Therapy to Take Down Tuberculosis

International audienceThe long-term treatment of tuberculosis (TB) sometimes leads to nonadherence to treatment, resulting in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. Inadequate bioavailability of the drug is the main factor for therapeutic failure, which leads to the development of drug-resistant cases. Therefore, there is an urgent need to design and develop novel antimycobacterial agents minimizing the period of treatment and reducing the propagation of resistance at the same time. Here, we report the development of original and noncytotoxic polycationic phosphorus dendrimers essentially of generations 0 and 1, but also of generations 2–4, with pyrrolidinium, piperidinium, and related cyclic amino groups on the surface, as new antitubercular agents active per se, meaning with intrinsic activity. The strategy is based on the phenotypic screening of a newly designed phosphorus dendrimer library (generations 0–4) against three bacterial strains: attenuated Mycobacterium tuberculosis H37Ra, virulent M. tuberculosis H37Rv, and Mangora bovis BCG. The most potent polycationic phosphorus dendrimers 1G0,HCl and 2G0,HCl are active against all three strains with minimum inhibitory concentrations (MICs) between 3.12 and 25.0 μg/mL. Both are irregularly shaped nanoparticles with highly mobile branches presenting a radius of gyration of 7 Å, a diameter of maximal 25 Å, and a solvent-accessible surface area of dominantly positive potential energy with very localized negative patches arising from the central N3P3 core, which steadily interacts with water molecules. The most interesting is 2G0,HCl, showing relevant efficacy against single-drug-resistant (SDR) M. tuberculosis H37Rv, resistant to rifampicin, isoniaid, ethambutol, or streptomycin. Importantly, 2G0,HCl displayed significant in vivo efficacy based on bacterial counts in lungs of infected Balb/C mice at a dose of 50 mg/kg oral administration once a day for 2 weeks and superior efficacy in comparison to ethambutol and rifampicin. This series of polycationic phosphorus dendrimers represents first-in-class drugs to treat TB infection, could fulfill the clinical candidate pipe of this high burden of infectious disease, and play a part in addressing the continuous demand for new drugs