Synthesis, antitubercular activity and docking study of novel cyclic azole substituted diphenyl ether derivatives

S.G. Kini, A.R. Bhat, B. Bryant, J.S. Williamson, F.E. Dayan

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives and determine their activity against H37Rv strain of Mycobacterium. All 10 compounds inhibited the growth of the H37Rv strain of mycobacterium at concentrations as low as 1 μg/mL. This level of activity was found comparable to the reference drugs rifampicin and isoniazid at the same concentration. Molecular modeling of the binding of the diphenyl ether derivatives on enoyl-ACP reductase, the molecular target site of triclosan, indicated that these compounds fit within the binding domain occupied by triclosan. Hence the diphenyl ether derivatives tested in this study were docked to ENR and the binding of the diphenyl ether derivatives was also estimated using a variety of scoring functions that have been compiled into the single consensus score. As the scores ranged from 47.27% to 65.81%, these bioactive compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential use as new antitubercular drugs. © 2008 Elsevier Masson SAS.
Original languageEnglish
Pages (from-to)492-500
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume44
Issue number2
DOIs
Publication statusPublished - 2009

Fingerprint

Azoles
Triclosan
Derivatives
Mycobacterium
Mycobacterium tuberculosis
Tuberculosis
Pharmaceutical Preparations
Antitubercular Agents
Molecular modeling
Isoniazid
Rifampin
Medical problems
Oxidoreductases
phenyl ether
Growth
Therapeutics

Cite this

@article{a473f06befaf44c68258f37498c2871a,
title = "Synthesis, antitubercular activity and docking study of novel cyclic azole substituted diphenyl ether derivatives",
abstract = "The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives and determine their activity against H37Rv strain of Mycobacterium. All 10 compounds inhibited the growth of the H37Rv strain of mycobacterium at concentrations as low as 1 μg/mL. This level of activity was found comparable to the reference drugs rifampicin and isoniazid at the same concentration. Molecular modeling of the binding of the diphenyl ether derivatives on enoyl-ACP reductase, the molecular target site of triclosan, indicated that these compounds fit within the binding domain occupied by triclosan. Hence the diphenyl ether derivatives tested in this study were docked to ENR and the binding of the diphenyl ether derivatives was also estimated using a variety of scoring functions that have been compiled into the single consensus score. As the scores ranged from 47.27{\%} to 65.81{\%}, these bioactive compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential use as new antitubercular drugs. {\circledC} 2008 Elsevier Masson SAS.",
author = "S.G. Kini and A.R. Bhat and B. Bryant and J.S. Williamson and F.E. Dayan",
note = "Cited By :52 Export Date: 10 November 2017 CODEN: EJMCA Correspondence Address: Kini, S.G.; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal, 576 104 Karnataka, India; email: suvarna_kini@yahoo.com Chemicals/CAS: enoyl acyl carrier protein reductase (NADH), 37251-08-4; isoniazid, 54-85-3, 62229-51-0, 65979-32-0; rifampicin, 13292-46-1; Antitubercular Agents; Azoles; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), 1.3.1.9; Phenyl Ethers; phenyl ether, 101-84-8 References: Wolinsky, E., (1992) Cecil Textbook of Medicine, 2, pp. 1733-1742. , Wyangaarden J.B., Smith Jr. L.H., and Bennett J.C. (Eds), W.B. Saunders Company, Philadelphia, PA; Sensi, P., Grass, I.G.G., (1996) Burger's Medicinal Chemistry and Drug Discovery, 2, pp. 575-635. , Burger A., and Wolff M.E. (Eds), John Wiley & Sons, New York; Bloom, B.R., Murray, C.J.L., Tuberculosis: commentary on a reemergent killer (1992) Science, 257, pp. 1055-1064; Okada, M., Kobayashi, K., Recent progress in mycobacteriology (2007) Kekkaku (Japanese Journal), 82 (10), pp. 783-799; (1997) World Health Organization Report on TB epidemic, , Global TB Programme, World Health Oraganization, Geneva; World Health Organisation, Tuberculosis, Fact Sheet No. 104, 2007 (site accessed: <www.who.int/mediacentre/factsheets/who104/en/index.html>); ElSayed, K.A., Bartyzel, P., Shen, X.Y., Perry, T.L., Zjawiony, J.K., Hamann, M.T., Marine natural products as antituberculosis agents (2000) Tetrahedron, 56, pp. 949-953; Goldberg, M.J., Antituberculosis agents (1988) Med. Clin. North. Am., 72, pp. 661-668; Tomioka, H., Namba, K., Development of antitubercular drugs: current status and future prospects (2006) Kekkaku (Japanese Journal), 81 (12), pp. 753-774; Berning, S.E., The role of fluoroquinolones in tuberculosis today (2001) Drugs, 61, pp. 9-18; Reddy, V.M., Nadadhur, G., Daneluzzi, D.D., Osullivan, J.F., Gangadharam, P.R.J., Antituberculosis activities of clofazimine and its new analogs B4154 and B4157 (1996) Antimicrob. Agents Chemother., 40, pp. 633-636; Barry, C.E., New horizons in the treatment of tuberculosis (1997) Biochem. Pharmacol., 54, pp. 1165-1172; Pasquato, K.F.M., Ferreira, E.I., An approach for the rational design of new antitubercular agents (2001) Curr. Drug Targets, 2, pp. 427-437; Schroeder, E.K., de Souza, N., Santos, D.D., Blanchard, J.S., Basso, L.A., Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis (2002) Curr. Pharm. Biotechnol., 3 (3), pp. 197-225; Barry III, C.E., Lee, R.E., Mdluli, K., Sampson, A.E., Schroeder, B.G., Slayden, R.A., Yaun, Y., Mycolic acid structure, biosynthesis and physiological functions (1998) Prog. Lipid Res., 37, pp. 143-179; Kolattukudy, P.E., Fernandes, N.D., Azad, A.K., Fitzmaurice, A.M., Sirakova, T.D., Biochemistry and molecular genetics of cell-wall lipid biosynthesis in mycobacteria (1997) Mol. Microbiol., 24, pp. 263-270; Bergler, H., Fuchsbichler, S., Hogenauer, G., Turnowsky, F., The enoyl-[acyl-carrier-protein] reductase (FabI) of Escherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA (1996) Eur. J. Biochem., 242, pp. 689-694; Stewart, M.J., Parikh, S., Xiao, G., Tonge, P.J., Kisker, C., Structural basis and mechanism of enoyl reductase inhibition by triclosan (1999) J. Mol. Biol., 290, pp. 859-865; Rozwarski, D.A., Vilcheze, C., Sugantino, M., Bittman, R., Sacchettini, J.C., Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty substrate (1999) J. Biol. Chem., 274, pp. 15582-15589; Boshoff, H.I., Mizrahi, V., Barry III, C.E., Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I (2002) J. Bacteriol., 184, pp. 2167-2172; Zimhony, O., Cox, J.S., Welch, J.T., Vilcheze, C., Jacobs Jr., W.R., Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis (2000) Nat. Med., 6, pp. 1043-1047; Schweizer, H.P., Triclosan: a widely used biocide and its link to antibiotics (2001) FEMS Microbiol. Lett., 202, pp. 1-7; Regos, J., Zak, O., Solf, R., Vischer, W.A., Weirich, E.G., Antimicrobial spectrum of triclosan, a broad-spectrum antimicrobial agent for topical application. II. Comparison with some other antimicrobial agents (1979) Dermatologica, 1158, pp. 72-79; Vischer, W.A., Regos, J., Antimicrobial spectrum of triclosan, a broad-spectrum antimicrobial agent for topical application (1974) Zentralbl. Bakteriol. [Orig A], 226, pp. 376-389; McMurry, L.M., Oethinger, M., Levy, S.B., Triclosan targets lipid synthesis (1998) Nature, 394, pp. 531-532; Heath, R.J., Yu, Y.T., Shapiro, M.A., Olson, E., Rock, C.O., Broad spectrum antimicrobial biocides target the FabI component of fatty acid synthesis (1998) J. Biol. Chem., 273, pp. 30316-30320; Levy, C.W., Roujeinikova, A., Sedelnikova, S., Baker, P.J., Stuitje, A.R., Molecular basis of triclosan activity (1999) Nature, 398, pp. 383-384; Roujeinikova, A., Levy, C.W., Rowsell, S., Sedelnikova, S., Baker, P.J., Minshull, C.A., Mistry, A., Rice, D.W., Crystallographic analysis of triclosan bound to enoyl reductase (1999) J. Mol. Biol., 294, pp. 527-535; Heath, R.J., Li, J., Roland, G.E., Rock, C.O., Inhibition of the Staphylococcus aureus NADPH-dependent enoyl-acyl carrier protein reductase by triclosan and hexachlorophene (2001) J. Biol. Chem., 275, pp. 4654-4659; Marcinkeviciene, J., Jiang, W., Kopcho, L.M., Locke, G., Luo, Y., Enoyl-ACP reductase (FabI) of Haemophilus influenzae: steady-state kinetic mechanism and inhibition by triclosan and hexachlorophene (2001) Arch. Biochem. Biophys., 390, pp. 101-108; McMurry, L.M., McDermott, P.F., Levy, S.B., Genetic evidence that InhA of Mycobacterium smegmatis is a target for triclosan (1999) Antimicrob. Agents Chemother., 43, pp. 711-713; Parikh, S.L., Xiao, G., Tonge, P.J., Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid (2000) Biochemistry, 39, pp. 7645-7650; Kuo, M.R., Morbidoni, H.R., Alland, D., Sneddon, S.F., Gourlie, B.B., Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data (2003) J. Biol. Chem., 278, pp. 20851-20859; Surolia, N., Surolia, A., Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum (2001) Nat. Med., 7, pp. 167-173; Kapoor, M., Dar, M.J., Surolia, N., Surolia, A., Kinetic determinants of the interaction of enoyl-ACP reductase from Plasmodium falciparum with its substrates and inhibitors (2001) Biochem. Biophys. Res. Commun., 289, pp. 832-837; Perozzo, R., Kuo, M., bir Singh Sidhu, A., Valiyaveettil, J.T., Bittman, R., Jacobs Jr., W.R., Fidock, D.A., Sacchettini, J.C., Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl ACP reductase (2002) J. Biol. Chem., 277, p. 13106; Vincent, C.B., Twomey, D., Derivatives of diploicin (1950) Proc. Royal Irish Acad., 53 B, pp. 55-59; Dosages and Pharmacokinetics of Antituberculosis medications - A Report in India, , http://www.angelfire.com/indie/tbindia/attdrugs.html, 13.06.2006 site accessed; Qiu, X., Janson, C.A., Court, R.I., Smyth, M.G., Payne, D.J., Abdel-Meguid, S.S., Molecular basis for triclosan activity involves a flipping loop in the active site (1999) Protein Sci., 8, pp. 2529-2532; Rarey, M., Kramer, B., Lengauer, T., Klebe, G.A., Fast flexible docking method using an incremental construction algorithm (1996) J. Mol. Biol., 261, pp. 470-489; Kramer, B., Rarey, M., Lengauer, T., Evaluation of the FlexX incremental construction algorithm for protein-ligand docking. Proteins: structure, function, and genetics (1999) J. Mol. Biol., 37, pp. 228-241; Bissantz, C., Folkers, G., Rognan, D., Protein-based virtual screening of chemical databases. Part 1. Evaluation of different docking/scoring combinations (2000) J. Med. Chem., 43, pp. 4759-4767; Heath, R.J., Rubin, J.R., Holland, D.R., Zhang, E., Snow, M.E., Rock, C.O., Mechanism of triclosan inhibition of bacterial fatty acid synthesis (1999) J. Biol. Chem., 274, pp. 11110-11114; Sivarana, S., Sullivan, T.J., Johnson, F., Novichenok, P., Cui, G., Simmerling, C., Tonge, P.J., Inhibition of the bacterial enoyl reductase FabI by triclosan: a structure-reactivity analysis of FabI inhibition by triclosan analogues (2004) J. Med. Chem., 47, pp. 509-518; Furniss, B.S., Hannaford, A.J., Rogers, V., Smith, P.W.G., Tatchell, A.R., Aromatic carboxylic acids (1980) Vogel's Text Book of Practical Organic Chemistry. fourth ed., , Longman Group Limited, London p. 824; Udupi, R., (1995) Studies on the Synthesis of Substituted Triazoles, Azetidinones, Quinazolinones and Related Compounds for Possible Antitubercular Activity and other Pharmacological Profiles, , Ph.D. Thesis; Watt, B., Rayner, A., Harris, G., Mackie, McCartney, (1996) Practical Medical Microbiology, pp. 331-335. , Colle J.G., Fraser A.G., Marmion B.P., and Simmons A. (Eds), Churchill Livingstone, New York (Chapter18); Edsall, J.T., Flory, P.J., Kendrew, J.C., Liquori, A.M., Nemethy, G., Ramachandran, G.N., Scheraga, H.A., A proposal of standard conventions and nomenclature for the description of polypeptide conformations (1966) J. Biol. Chem., 241, pp. 1004-1008; Purcell, W., Singer, J.A., Brief review and table of semiempirical parameters used in the Hueckel molecular orbital method (1967) J. Chem. Eng. Data., 12, pp. 235-246; Cieplak, P., Cornell, W.D., Bayly, C., Kollman, P.A., Application of the multimolecule and multiconformational RESP methodology to biopolymers: charge derivation for DNA, RNA, and proteins (1995) J. Comput. Chem., 16, pp. 1357-1377; Leach, A.R., Kuntz, I., Conformational analysis of flexible ligands in macromolecular receptor sites (1992) J. Comput. Chem., 13, pp. 730-748; Rarey, M., Kramer, B., Lengauer, T., Multiple automatic base selection: protein-ligand docking based on incremental construction without manual intervention (1997) J. Comput.-Aided Mol. Des., 11, pp. 369-384",
year = "2009",
doi = "10.1016/j.ejmech.2008.04.013",
language = "English",
volume = "44",
pages = "492--500",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
number = "2",

}

Synthesis, antitubercular activity and docking study of novel cyclic azole substituted diphenyl ether derivatives. / Kini, S.G.; Bhat, A.R.; Bryant, B.; Williamson, J.S.; Dayan, F.E.

In: European Journal of Medicinal Chemistry, Vol. 44, No. 2, 2009, p. 492-500.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis, antitubercular activity and docking study of novel cyclic azole substituted diphenyl ether derivatives

AU - Kini, S.G.

AU - Bhat, A.R.

AU - Bryant, B.

AU - Williamson, J.S.

AU - Dayan, F.E.

N1 - Cited By :52 Export Date: 10 November 2017 CODEN: EJMCA Correspondence Address: Kini, S.G.; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal, 576 104 Karnataka, India; email: suvarna_kini@yahoo.com Chemicals/CAS: enoyl acyl carrier protein reductase (NADH), 37251-08-4; isoniazid, 54-85-3, 62229-51-0, 65979-32-0; rifampicin, 13292-46-1; Antitubercular Agents; Azoles; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), 1.3.1.9; Phenyl Ethers; phenyl ether, 101-84-8 References: Wolinsky, E., (1992) Cecil Textbook of Medicine, 2, pp. 1733-1742. , Wyangaarden J.B., Smith Jr. L.H., and Bennett J.C. (Eds), W.B. Saunders Company, Philadelphia, PA; Sensi, P., Grass, I.G.G., (1996) Burger's Medicinal Chemistry and Drug Discovery, 2, pp. 575-635. , Burger A., and Wolff M.E. (Eds), John Wiley & Sons, New York; Bloom, B.R., Murray, C.J.L., Tuberculosis: commentary on a reemergent killer (1992) Science, 257, pp. 1055-1064; Okada, M., Kobayashi, K., Recent progress in mycobacteriology (2007) Kekkaku (Japanese Journal), 82 (10), pp. 783-799; (1997) World Health Organization Report on TB epidemic, , Global TB Programme, World Health Oraganization, Geneva; World Health Organisation, Tuberculosis, Fact Sheet No. 104, 2007 (site accessed: <www.who.int/mediacentre/factsheets/who104/en/index.html>); ElSayed, K.A., Bartyzel, P., Shen, X.Y., Perry, T.L., Zjawiony, J.K., Hamann, M.T., Marine natural products as antituberculosis agents (2000) Tetrahedron, 56, pp. 949-953; Goldberg, M.J., Antituberculosis agents (1988) Med. Clin. North. Am., 72, pp. 661-668; Tomioka, H., Namba, K., Development of antitubercular drugs: current status and future prospects (2006) Kekkaku (Japanese Journal), 81 (12), pp. 753-774; Berning, S.E., The role of fluoroquinolones in tuberculosis today (2001) Drugs, 61, pp. 9-18; Reddy, V.M., Nadadhur, G., Daneluzzi, D.D., Osullivan, J.F., Gangadharam, P.R.J., Antituberculosis activities of clofazimine and its new analogs B4154 and B4157 (1996) Antimicrob. Agents Chemother., 40, pp. 633-636; Barry, C.E., New horizons in the treatment of tuberculosis (1997) Biochem. Pharmacol., 54, pp. 1165-1172; Pasquato, K.F.M., Ferreira, E.I., An approach for the rational design of new antitubercular agents (2001) Curr. Drug Targets, 2, pp. 427-437; Schroeder, E.K., de Souza, N., Santos, D.D., Blanchard, J.S., Basso, L.A., Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis (2002) Curr. Pharm. Biotechnol., 3 (3), pp. 197-225; Barry III, C.E., Lee, R.E., Mdluli, K., Sampson, A.E., Schroeder, B.G., Slayden, R.A., Yaun, Y., Mycolic acid structure, biosynthesis and physiological functions (1998) Prog. Lipid Res., 37, pp. 143-179; Kolattukudy, P.E., Fernandes, N.D., Azad, A.K., Fitzmaurice, A.M., Sirakova, T.D., Biochemistry and molecular genetics of cell-wall lipid biosynthesis in mycobacteria (1997) Mol. Microbiol., 24, pp. 263-270; Bergler, H., Fuchsbichler, S., Hogenauer, G., Turnowsky, F., The enoyl-[acyl-carrier-protein] reductase (FabI) of Escherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA (1996) Eur. J. Biochem., 242, pp. 689-694; Stewart, M.J., Parikh, S., Xiao, G., Tonge, P.J., Kisker, C., Structural basis and mechanism of enoyl reductase inhibition by triclosan (1999) J. Mol. Biol., 290, pp. 859-865; Rozwarski, D.A., Vilcheze, C., Sugantino, M., Bittman, R., Sacchettini, J.C., Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty substrate (1999) J. Biol. Chem., 274, pp. 15582-15589; Boshoff, H.I., Mizrahi, V., Barry III, C.E., Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I (2002) J. Bacteriol., 184, pp. 2167-2172; Zimhony, O., Cox, J.S., Welch, J.T., Vilcheze, C., Jacobs Jr., W.R., Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis (2000) Nat. Med., 6, pp. 1043-1047; Schweizer, H.P., Triclosan: a widely used biocide and its link to antibiotics (2001) FEMS Microbiol. Lett., 202, pp. 1-7; Regos, J., Zak, O., Solf, R., Vischer, W.A., Weirich, E.G., Antimicrobial spectrum of triclosan, a broad-spectrum antimicrobial agent for topical application. II. Comparison with some other antimicrobial agents (1979) Dermatologica, 1158, pp. 72-79; Vischer, W.A., Regos, J., Antimicrobial spectrum of triclosan, a broad-spectrum antimicrobial agent for topical application (1974) Zentralbl. Bakteriol. [Orig A], 226, pp. 376-389; McMurry, L.M., Oethinger, M., Levy, S.B., Triclosan targets lipid synthesis (1998) Nature, 394, pp. 531-532; Heath, R.J., Yu, Y.T., Shapiro, M.A., Olson, E., Rock, C.O., Broad spectrum antimicrobial biocides target the FabI component of fatty acid synthesis (1998) J. Biol. Chem., 273, pp. 30316-30320; Levy, C.W., Roujeinikova, A., Sedelnikova, S., Baker, P.J., Stuitje, A.R., Molecular basis of triclosan activity (1999) Nature, 398, pp. 383-384; Roujeinikova, A., Levy, C.W., Rowsell, S., Sedelnikova, S., Baker, P.J., Minshull, C.A., Mistry, A., Rice, D.W., Crystallographic analysis of triclosan bound to enoyl reductase (1999) J. Mol. Biol., 294, pp. 527-535; Heath, R.J., Li, J., Roland, G.E., Rock, C.O., Inhibition of the Staphylococcus aureus NADPH-dependent enoyl-acyl carrier protein reductase by triclosan and hexachlorophene (2001) J. Biol. Chem., 275, pp. 4654-4659; Marcinkeviciene, J., Jiang, W., Kopcho, L.M., Locke, G., Luo, Y., Enoyl-ACP reductase (FabI) of Haemophilus influenzae: steady-state kinetic mechanism and inhibition by triclosan and hexachlorophene (2001) Arch. Biochem. Biophys., 390, pp. 101-108; McMurry, L.M., McDermott, P.F., Levy, S.B., Genetic evidence that InhA of Mycobacterium smegmatis is a target for triclosan (1999) Antimicrob. Agents Chemother., 43, pp. 711-713; Parikh, S.L., Xiao, G., Tonge, P.J., Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid (2000) Biochemistry, 39, pp. 7645-7650; Kuo, M.R., Morbidoni, H.R., Alland, D., Sneddon, S.F., Gourlie, B.B., Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data (2003) J. Biol. Chem., 278, pp. 20851-20859; Surolia, N., Surolia, A., Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum (2001) Nat. Med., 7, pp. 167-173; Kapoor, M., Dar, M.J., Surolia, N., Surolia, A., Kinetic determinants of the interaction of enoyl-ACP reductase from Plasmodium falciparum with its substrates and inhibitors (2001) Biochem. Biophys. Res. Commun., 289, pp. 832-837; Perozzo, R., Kuo, M., bir Singh Sidhu, A., Valiyaveettil, J.T., Bittman, R., Jacobs Jr., W.R., Fidock, D.A., Sacchettini, J.C., Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl ACP reductase (2002) J. Biol. Chem., 277, p. 13106; Vincent, C.B., Twomey, D., Derivatives of diploicin (1950) Proc. Royal Irish Acad., 53 B, pp. 55-59; Dosages and Pharmacokinetics of Antituberculosis medications - A Report in India, , http://www.angelfire.com/indie/tbindia/attdrugs.html, 13.06.2006 site accessed; Qiu, X., Janson, C.A., Court, R.I., Smyth, M.G., Payne, D.J., Abdel-Meguid, S.S., Molecular basis for triclosan activity involves a flipping loop in the active site (1999) Protein Sci., 8, pp. 2529-2532; Rarey, M., Kramer, B., Lengauer, T., Klebe, G.A., Fast flexible docking method using an incremental construction algorithm (1996) J. Mol. Biol., 261, pp. 470-489; Kramer, B., Rarey, M., Lengauer, T., Evaluation of the FlexX incremental construction algorithm for protein-ligand docking. Proteins: structure, function, and genetics (1999) J. Mol. Biol., 37, pp. 228-241; Bissantz, C., Folkers, G., Rognan, D., Protein-based virtual screening of chemical databases. Part 1. Evaluation of different docking/scoring combinations (2000) J. Med. Chem., 43, pp. 4759-4767; Heath, R.J., Rubin, J.R., Holland, D.R., Zhang, E., Snow, M.E., Rock, C.O., Mechanism of triclosan inhibition of bacterial fatty acid synthesis (1999) J. Biol. Chem., 274, pp. 11110-11114; Sivarana, S., Sullivan, T.J., Johnson, F., Novichenok, P., Cui, G., Simmerling, C., Tonge, P.J., Inhibition of the bacterial enoyl reductase FabI by triclosan: a structure-reactivity analysis of FabI inhibition by triclosan analogues (2004) J. Med. Chem., 47, pp. 509-518; Furniss, B.S., Hannaford, A.J., Rogers, V., Smith, P.W.G., Tatchell, A.R., Aromatic carboxylic acids (1980) Vogel's Text Book of Practical Organic Chemistry. fourth ed., , Longman Group Limited, London p. 824; Udupi, R., (1995) Studies on the Synthesis of Substituted Triazoles, Azetidinones, Quinazolinones and Related Compounds for Possible Antitubercular Activity and other Pharmacological Profiles, , Ph.D. Thesis; Watt, B., Rayner, A., Harris, G., Mackie, McCartney, (1996) Practical Medical Microbiology, pp. 331-335. , Colle J.G., Fraser A.G., Marmion B.P., and Simmons A. (Eds), Churchill Livingstone, New York (Chapter18); Edsall, J.T., Flory, P.J., Kendrew, J.C., Liquori, A.M., Nemethy, G., Ramachandran, G.N., Scheraga, H.A., A proposal of standard conventions and nomenclature for the description of polypeptide conformations (1966) J. Biol. Chem., 241, pp. 1004-1008; Purcell, W., Singer, J.A., Brief review and table of semiempirical parameters used in the Hueckel molecular orbital method (1967) J. Chem. Eng. Data., 12, pp. 235-246; Cieplak, P., Cornell, W.D., Bayly, C., Kollman, P.A., Application of the multimolecule and multiconformational RESP methodology to biopolymers: charge derivation for DNA, RNA, and proteins (1995) J. Comput. Chem., 16, pp. 1357-1377; Leach, A.R., Kuntz, I., Conformational analysis of flexible ligands in macromolecular receptor sites (1992) J. Comput. Chem., 13, pp. 730-748; Rarey, M., Kramer, B., Lengauer, T., Multiple automatic base selection: protein-ligand docking based on incremental construction without manual intervention (1997) J. Comput.-Aided Mol. Des., 11, pp. 369-384

PY - 2009

Y1 - 2009

N2 - The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives and determine their activity against H37Rv strain of Mycobacterium. All 10 compounds inhibited the growth of the H37Rv strain of mycobacterium at concentrations as low as 1 μg/mL. This level of activity was found comparable to the reference drugs rifampicin and isoniazid at the same concentration. Molecular modeling of the binding of the diphenyl ether derivatives on enoyl-ACP reductase, the molecular target site of triclosan, indicated that these compounds fit within the binding domain occupied by triclosan. Hence the diphenyl ether derivatives tested in this study were docked to ENR and the binding of the diphenyl ether derivatives was also estimated using a variety of scoring functions that have been compiled into the single consensus score. As the scores ranged from 47.27% to 65.81%, these bioactive compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential use as new antitubercular drugs. © 2008 Elsevier Masson SAS.

AB - The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives and determine their activity against H37Rv strain of Mycobacterium. All 10 compounds inhibited the growth of the H37Rv strain of mycobacterium at concentrations as low as 1 μg/mL. This level of activity was found comparable to the reference drugs rifampicin and isoniazid at the same concentration. Molecular modeling of the binding of the diphenyl ether derivatives on enoyl-ACP reductase, the molecular target site of triclosan, indicated that these compounds fit within the binding domain occupied by triclosan. Hence the diphenyl ether derivatives tested in this study were docked to ENR and the binding of the diphenyl ether derivatives was also estimated using a variety of scoring functions that have been compiled into the single consensus score. As the scores ranged from 47.27% to 65.81%, these bioactive compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential use as new antitubercular drugs. © 2008 Elsevier Masson SAS.

U2 - 10.1016/j.ejmech.2008.04.013

DO - 10.1016/j.ejmech.2008.04.013

M3 - Article

VL - 44

SP - 492

EP - 500

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

IS - 2

ER -