Quinoline or 1-aza-naphthalene is a weak tertiary base. Quinoline ring has been found to possess antimalarial, anti-bacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, and analgesic activity. Quinoline not only has a wide range of biological and pharmacological activities but there are several established protocols for the synthesis of this ring. The article aims at highlighting these very diversities of the ring.

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.DNA ligases are vital enzymes in replication and repair and catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA through similar mechanisms (1). These enzymes can be divided into two classes, viz. NAD ؉ -and ATP-dependent ligases, based on the cofactor specificities (2). NAD ؉ -dependent DNA ligases, commonly called LigA, are found in bacteria and entomopoxviruses (3, 20), whereas ATP-dependent ligases are ubiquitous (3). Although there is little sequence homology between the eubacterial and eukaryotic enzymes, they exhibit some structural homology in specific domains (4, 5). The mechanistic steps involved in enzymatic action are also broadly conserved. Briefly, in the first step, the mode of action involves an attack on the ␣-phosphorus of ATP or NAD ؉ by the enzyme, releasing pyrophosphate or NMN and forming a ligase-adenylate intermediate. In the second step, the bound AMP is transferred to the 5Ј-end of DNA to form a DNAadenylate intermediate. AMP is released in the third step, where the protein catalyzes the joining of the 3Ј-nicked DNA to the DNA-adenylate intermediate. These steps involve large conformational changes and also encircling and partial unwinding of the nicked DNA substrate (6 -8).Some bacteria code for both NAD ؉ -and ATP-dependent DNA ligases (3, 9). Mycobacterium tuberculosis codes for at least three different types of ATP-dependent ligases and a NAD ϩ -dependent ligase (10, 11). Gene knockout and other studies have shown LigA to be indispensable in several bacteria, including Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and M. tuberculosis (10,(12)(13)(14)(15).No LigA structure from mycobacterial sources is available to date. However, the crystal structure of the full-length protein is available for the Thermus filifo...

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.

Mycobacterium tuberculosis codes for an essential NAD+-dependent DNA ligase (MtuLigA) which is a novel, validated, and attractive drug target. We created mutants of the enzyme by systematically deleting domains from the C-terminal end of the enzyme to probe for their functional roles in the DNA nick joining reaction. Deletion of just the BRCT domain from MtuLigA resulted in total loss of activity in in vitro assays. However, the mutant could form an AMP-ligase intermediate that suggests that the defects caused by deletion of the BRCT domain occur primarily at steps after enzyme adenylation. Furthermore, genetic complementation experiments using a LigA deficient E. coli strain demonstrates that the BRCT domain of MtuLigA is necessary for bacterial survival in contrast to E. coli and T. filiformis LigA, respectively. We also report the identification, through virtual screening, of a novel N-substituted tetracyclic indole that competes with NAD+ and inhibits the enzyme with IC50 in the low muM range. It exhibits approximately 15-fold better affinity for MtuLigA compared to human DNA ligase I. In vivo assays using LigA deficient S. typhimurium and E. coli strains suggest that the observed antibacterial activity of the inhibitor arises from specific inhibition of LigA over ATP ligases in the bacteria. In silico ligand-docking studies suggest that the exquisite specificity of the inhibitor arises on account of its mimicking the interactions of NAD+ with MtuLigA. An analysis of conserved water in the binding site of the enzyme suggests strategies for synthesis of improved inhibitors with better specificity and potency.

Poly(A) polymerases (PAPs) are found in most living organisms and have important roles in RNA function and metabolism. Here we report the crystal structure of human PAPD1, a noncanonical PAP that can polyadenylate RNAs in the mitochondria (also known as mtPAP) and oligouridylate histone mRNAs (TUTase1). The overall structure of the palm and fingers domains is similar to that in the canonical PAPs. The active site is located at the interface between the two domains, with a large pocket that can accommodate the substrates. The structure reveals the presence of a previously unrecognized domain in the N-terminal region of PAPD1, with a backbone-fold that is similar to that of RNP-type RNA binding domains. This domain (named the RL domain), together with a β-arm insertion in the palm domain, contributes to dimerization of PAPD1. Surprisingly, our mutagenesis and biochemical studies show that dimerization is required for the catalytic activity of PAPD1.