N. S. Hari Narayana Moorthy

Bio: N. S. Hari Narayana Moorthy is an academic researcher from University of Porto. The author has contributed to research in topics: Quantitative structure–activity relationship & Pharmacophore. The author has an hindex of 15, co-authored 59 publications receiving 715 citations. Previous affiliations of N. S. Hari Narayana Moorthy include Indira Gandhi National Tribal University & Rajiv Gandhi Proudyogiki Vishwavidyalaya.

Human CDC2-Like Kinase 1 (CLK1): A Novel Target for Alzheimer’s Disease

Abstract: The cdc2-like kinases (CLKs) are an evolutionarily conserved group of dual specificity kinases belonging to the CMGC (cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases). The CLK family consists of four isoforms namely CLK1, CLK2, CLK3 and CLK4. The human CLK1 encoded protein comprises 454 amino acids and the catalytic domain of CLK1 exhibits the typical protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phosphorylate exogenous substrates on serine and threonine residues. CLK1 plays an important role in the regulation of RNA splicing through phosphorylation of members of the serine and arginine-rich (SR) family of splicing factors. CLK1 is involved in the pathophysiology of Alzheimer's disease by phosphorylating the serine residue in SR proteins. Nuclear speckles of the nucleoplasm contain the stored form of SR proteins and are moderately responsible for the choice of splicing sites during pre-mRNA splicing. Hence, the inhibition of CLK1 can be used as a therapeutic strategy for Alzheimer's disease. Many natural and synthetic molecules are reported to possess CLK1 inhibitory activity. Some specific examples are Marine alkaloid Leucettamine B and KH-CB19. Leucettamine B is a potent inhibitor of CLK1 (15 nM), Dyrk1A (40 nM), and Dyrk2 (35 nM) and a moderate inhibitor of CLK3 (4.5 µM) whereas KH-CB19 is a highly specific and potent inhibitor of the CLK1/CLK4. X-ray crystallographic studies have revealed the binding mode of marine sponge metabolite hymenialdisine and a dichloroindolyl enamino nitrile (KH-CB19) to CLK1. This review focuses on the role of CLKs in the pathophysiology of Alzheimer's disease and therapeutic potential of targeting CLK1 in Alzheimer's disease drug discovery and development. In addition, the recent developments in drug discovery efforts targeting human CLK1 are also highlighted.

Viral M2 ion channel protein: a promising target for anti-influenza drug discovery.

Abstract: Influenza virus is an important RNA virus causing pandemics (Spanish Flu (1918), Asian Flu (1957), Hong Kong Flu (1968) and Swine Flu (2009)) over the last decades. Due to the spontaneous mutations of these viral proteins, currently available antiviral and anti-influenza drugs quickly develop resistance. To account this, only limited antiinfluenza drugs have been approved for the therapeutic use. These include amantadine and rimantadine (M2 proton channel blockers), zanamivir, oseltamivir and peramivir (neuraminidase inhibitors), favipravir (polymerase inhibitor) and laninamivir. This review provides an outline on the strategies to develop novel, potent chemotherapeutic agents against M2 proton channel. Primarily, the M2 proton channel blockers elicit pharmacological activity through destabilizing the helices by blocking the proton transport across the transmembrane. The biologically important compounds discovered using the scaffolds such as bisnoradmantane, noradamantane, triazine, spiroadamantane, isoxazole, amino alcohol, azaspiro, spirene, pinanamine, etc are reported to exhibit anti-influenza activity against wild or mutant type (S31N and V27A) of M2 proton channel protein. The reported studies explained that the adamantane based compounds (amantadine and rimantadine) strongly interact with His37 (through hydrogen bonding) and Ala30, Ile33 and Gly34 residues (hydrophobic interactions). The adamantane and the non-adamantane scaffolds fit perfectly in the active site pocket present in the wild type and the charged amino groups (ammonium) create positive electrostatic potential, which blocks the transport of protons across the pore. In the mutated proteins, larger or smaller binding pocket are created by small or large mutant residues, which do not allow the molecules fit in the active site. This causes the channel to be unblocked and the protons are allowed to transfer inside the pore. The structural analysis of the M2 proton channel blockers illustrated that the adamantane derivatives have action against both influenza A and B, but have no effect on the mutants.

6H-Indolo[2,3-b]Quinoxalines: DNA and Protein Interacting Scaffold for Pharmacological Activities

Abstract: 6H-Indolo[2,3-b]quinoxaline, a planar fused heterocyclic compound exhibits a wide variety of pharmacological activities. The mechanism of pharmacological action exerted by these compounds is predominantly DNA intercalation. The thermal stability of the intercalated complex (DNA and 6H-indolo[2,3-b]quinoxaline derivatives) is an important parameter for the elucidation of anticancer, antiviral and other activities. This thermal stability of the 6H-indolo[2,3- b]quinoxaline-DNA complex depends on the type of substituents and side chains attached to the 6H-indolo[2,3- b]quinoxaline nucleus and also the orientation of the side chain towards the GC rich minor groove of the DNA. Highly active 6H-indolo[2,3-b]quinoxaline derivatives such as NCA0424, B-220 and 9-OH-B-220 have shown good binding affinity to DNA as evident from high thermal stability of compound-DNA complex. Interestingly, these compounds possessed poor inhibitory activity on topoisomerase II enzyme but have significant MDR modulating activity. This review establishes '6H-indolo[2,3-b]quinoxaline' as a valuable template for design and development of novel molecules with different biological activities.

Synthesis of some coumarinyl chalcones and their antiproliferative activity against breast cancer cell lines

Abstract: A series of coumarinyl chalcones derivatives were synthesized and evaluated for their antiproliferative activities on three different breast cancer cell lines (MDA-MB231, MDA-MB468, MCF7) and one non-cancer breast epithelial cell line (184B5). The coumarinyl derivatives exhibited anticancer activity against breast cancer cell lines at a micromolar range. A structure-activity relationship (SAR) analysis was performed by studying the effect of substituents on their antiproliferative activities. One of the compound 3i bearing methoxy substitutions at the R1, R2 and R3 positions of the phenyl ring showed comparable potency to the reference drug cisplatin as well as a two-fold higher selectivity for the breast cancer cell lines than 184B5 cells.

QSAR analysis of 2-benzoxazolyl hydrazone derivatives for anticancer activity and its possible target prediction

Abstract: QSAR studies on a series of 2-benzoxazolyl hydrazone derivatives against various cancer cell lines were carried out to interpret the physicochemical properties responsible for the antitumor activity. The integy moments of the molecules (vsurf_ID8 and vsurf_IW6) reveals that the active site surface or the biological membrane where these compounds bind or penetrate must have a very specific and localized hydrophobic region. These integy moments reduce the interaction energy between the molecule and the water, which improve the antitumor activity. The potential energy descriptors indicate that the flexibility of the freely rotatable bonds is important for the interaction with the chemotherapeutic target and/or barriers to reach the target. Comparing the results obtained from this study and other QSAR studies addressed to similar compounds, we concluded that the benzoxazolyl derivatives may bind to the same target. The present analysis has shown that the antitumor activity can be improved with the presence of specific hydrophobic substituents and electro-donating groups nearby the hydrazone moiety. Moreover, the formation of an intramolecular hydrogen bond has a high impact on the pharmacological activity of these compounds. The information gathered from these studies provides useful information about the binding site of these compounds.

Ruthenium-catalyzed direct oxidative alkenylation of arenes through twofold C–H bond functionalization

Abstract: Significant progress has been accomplished in direct olefinations through twofold C–H bond functionalization of arenes and heteroarenes employing readily accessible, selective and relatively inexpensive ruthenium catalysts. Particularly, ruthenium(II) complexes have allowed challenging direct double C–H/C–H bond alkenylations of arenes with ample scope. These catalysts set the stage for step-economical C–H/C–H bond functionalization with electron-rich as well as electron-deficient arenes and heteroarenes, and, thereby, provide versatile access to diversely decorated styrenes.

Metabolism and function of phenazines in bacteria: impacts on the behavior of bacteria in the environment and biotechnological processes

Abstract: Phenazines constitute a large group of nitrogen-containing heterocyclic compounds produced by a diverse range of bacteria. Both natural and synthetic phenazine derivatives are studied due their impacts on bacterial interactions and biotechnological processes. Phenazines serve as electron shuttles to alternate terminal acceptors, modify cellular redox states, act as cell signals that regulate patterns of gene expression, contribute to biofilm formation and architecture, and enhance bacterial survival. Phenazines have diverse effects on eukaryotic hosts and host tissues, including the modification of multiple host cellular responses. In plants, phenazines also may influence growth and elicit induced systemic resistance. Here, we discuss emerging evidence that phenazines play multiple roles for the producing organism and contribute to their behavior and ecological fitness.

Current Developments of Coumarin Compounds in Medicinal Chemistry

Abstract: Coumarin compounds represent an important type of naturally occurring and synthetic oxygen-containing heterocycles with typical benzopyrone framework. This type of special benzopyrone structure enables its derivatives readily interact with a diversity of enzymes and receptors in organisms through weak bond interactions, thereby exhibit wide potentiality as medicinal drugs. So far, some coumarin-based drugs such as anticoagulant and antineurodegenerative agents have been extensively used in clinic. Coumarin-containing supramolecular medicinal agents as a new increasing expansion of supramolecular chemistry in pharmaceutical science have also been actively investigated in recent years. Coumarin-derived artificial ion receptors, fluorescent probes and biological stains are growing quickly and have a variety of potential applications in monitoring timely enzyme activity, complex biological events as well as accurate pharmacological and pharmacokinetic properties. This review provides a systematic summary and insight of the whole range of medicinal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of coumarinbased medicinal chemistry are also presented.

A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication

Abstract: Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo-based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.