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Medicinal Chemistry Research

, Volume 28, Issue 12, pp 2279–2293 | Cite as

Synthesis and antimycobacterial activity of disubstituted benzyltriazoles

  • Frans J. Smit
  • Ronnett Seldon
  • Janine Aucamp
  • Audrey Jordaan
  • Digby F. Warner
  • David D. N’DaEmail author
Original Research

Abstract

The increasing prevalence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB), serves as a strong incentive for the discovery and development of new agents for the treatment of this plight. In search for such drugs, we investigated a series of benzyltriazole derivatives. We herein report the design, synthesis and biological activity of disubstituted benzyltriazoles against the human virulent H37Rv strain of Mtb as well as the toxicity on human embryonic kidney (HEK-293) cells. The derivative 21 featuring trifluoromethyl substituent in para position on the phenyl ring and n-butyl chain in position 4 on the triazole ring was the most active with MIC90 and MIC99 values of 1.73 and 3.2 µM, respectively, in the albumin-free medium. It also displays high selectivity towards bacteria growth inhibition (SI > 58), thus stands as a better hit for further investigation, including lead optimization, DMPK parameters determination and assessment of its activity in animal models.

Keywords

Tuberculosis TB Drug discovery Benzyltriazole Click chemistry 

Notes

Acknowledgements

This work was funded by a South African National Research Foundation Grant to DDN’Da (UID 76443). The South African Medical Research Council is gratefully acknowledged for financial support of the antimycobacterial screening assays (SHIP-MRC grant to DFW). The authors thank Dr D. Otto for NMR analysis and Dr JHL Jordaan for MS analysis. Isoniazid was generously donated by Aspen Pharmacare (Port Elizabeth, South Africa).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2458_MOESM1_ESM.docx (41.6 mb)
Supplementary Information

References

  1. Abrahams GL, Kumar A, Savvi S, Hung AW, Wen S, Abell C, Barry III CE, Sherman DR, Boshoff HI, Mizrahi V (2012) Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening. Chem Biol 19(7):844–854PubMedPubMedCentralGoogle Scholar
  2. Ali AA, Gogoi D, Chaliha AK, Buragohain AK, Trivedi P, Saikia PJ, Gehlot PS, Kumar A, Chaturvedi V, Sarma D (2017) Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents. Bioorg Med Chem Lett 27:3698–3703Google Scholar
  3. Amir A, Rana K, Arya A, Kapoor N, Kumar H, Siddiqui MA (2014) Mycobacterium tuberculosis H37Rv: in silico drug targets identification by metabolic pathways analysis. J Evol Biol 2014:8Google Scholar
  4. Ballari MS, Herrera Cano N, Lopez AG, Wunderlin DA, Feresín GE, Santiago AN (2017) Green synthesis of potential antifungal agents: 2-benzyl substituted thiobenzoazoles. J Agric Food Chem 65(47):10325–10331PubMedGoogle Scholar
  5. Belz T, Ihmaid S, Al-Rawi J, Petrovski S (2013) Synthesis characterization and antibacterial, antifungal activity of N-(benzyl carbamoyl or carbamothioyl)-2-hydroxy substituted benzamide and 2-benzyl amino-substituted benzoxazines. Int J Med Chem 2013:436397PubMedPubMedCentralGoogle Scholar
  6. Boechat N, Ferreira VF, Ferreira SB, Ferreira MdLG, da Silva FdC, Bastos MM, Costa MdS, Lourenço MCS, Pinto AC, Krettli AU et al. (2011a) Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. J Med Chem 54(17):5988–5999PubMedGoogle Scholar
  7. Boechat N, Ferreira VF, Ferreira SB, Ferreira MdLG, da Silva FdC, Bastos MM, Costa MdS, Lourenço MCS, Pinto AC, Krettli AU et al. (2011b) Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. J Med Chem 54:5988–5999PubMedGoogle Scholar
  8. CDC (2018a) CDC | TB | Drug-resistant TB. Centers for Disease Control and Prevention, Atlanta, Georgia, US. https://www.cdc.gov/tb/topic/drtb/default.htm. Accessed 25 Jul 2019
  9. CDC (2018b) Treatment for TB Disease. Centers for Disease Control and Prevention, Atlanta, Georgia, US. https://www.cdc.gov/tb/topic/treatment/tbdisease.htm. Accessed 9 Oct 2018.
  10. Cheng YJ, Liu ZY, Liang HJ, Fang CT, Zhang NN, Zhang TY, Yan M (2019) Discovery of (3-Benzyl-5-hydroxyphenyl)carbamates as new antitubercular agents with potent in vitro and in vivo efficacy. Molecules 24(10):pii: E2021Google Scholar
  11. Collins L, Franzblau SG (1997) Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrobial agents Chemother 41(5):1004–1009Google Scholar
  12. Collins LA, Torrero MN, Franzblau SG (1998) Green fluorescent protein reporter microplate assay for high-throughput screening of compounds against Mycobacterium tuberculosis. Antimicrobial Agents Chemother 42(2):344–347Google Scholar
  13. Courtens C, Risseeuw M, Caljon G, Cos P, Van Calenbergh S (2018) Acyloxybenzyl and alkoxyalkyl prodrugs of a fosmidomycin surrogate as antimalarial and antitubercular agents. ACS Med Chem Lett 9(10):986–989PubMedPubMedCentralGoogle Scholar
  14. Dai Z-C, Chen Y-F, Zhang M, Li S-K, Yang T-T, Shen L, Wang J-X, Qian S-S, Zhu H-L, Ye Y-H (2015) Synthesis and antifungal activity of 1, 2, 3-triazole phenylhydrazone derivatives. Org Biomol Chem 13:477–486PubMedGoogle Scholar
  15. De Voss JJ, Rutter K, Schroeder BG, Su H, Zhu Y, Barry CE, III. 2000. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. In: Proceedings of the National Academy of Sciences of the United States of America. 97(3):1252–1257.Google Scholar
  16. Dheer D, Singh V, Shankar R (2017) Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg Chem 71:30–54PubMedGoogle Scholar
  17. Dockal M, Carter DC, Ruker F (2000) Conformational transitions of the three recombinant domains of human serum albumin depending on pH. J Biol Chem 275(5):3042–3050PubMedGoogle Scholar
  18. El Bissati K, Redel H, Ting L-M, Lykins JD, McPhillie MJ, Upadhya R, Woster PM, Yarlett N, Kim K, Weiss LM (2019) Novel synthetic polyamines have potent antimalarial activities in vitro and in vivo by decreasing intracellular spermidine and spermine concentrations. Front Cell Infect Microbiol 9(9):9PubMedPubMedCentralGoogle Scholar
  19. Fan Y-L, Wu J-B, Cheng X-W, Zhang F-Z, Feng L-S (2018) Fluoroquinolone derivatives and their anti-tubercular activities. Eur J Med Chem 146:554–563PubMedGoogle Scholar
  20. Franzblau SG, DeGroote MA, Cho SH, Andries K, Nuermberger E, Orme IM, Mdluli K, Angulo-Barturen I, Dick T, Dartois V et al. (2012) Comprehensive analysis of methods used for the evaluation of compounds against Mycobacterium tuberculosis. Tuberculosis 92(6):453–488PubMedGoogle Scholar
  21. Gallardo-Macias R, Kumar P, Jaskowski M, Richmann T, Shrestha R, Russo R, Singleton E, Zimmerman MD, Ho HP, Dartois V et al. (2019) Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent. Bioorg Med Chem Lett 29(4):601–606PubMedGoogle Scholar
  22. Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA (2015) Applications of fluorine in medicinal chemistry. J Med Chem 58(21):8315–8359PubMedGoogle Scholar
  23. Gombar VK, Enslein K (1996) Assessment of n-octanol/water partition coefficient: when is the assessment reliable? J Chem Inf Comput Sci 36(6):1127–1134PubMedGoogle Scholar
  24. Howson SE, Peter S (2010). Formation of benzyl azide from benzyl bromide; benzyl azide. ChemSpider - Synthetic.  https://doi.org/10.1039/SP408
  25. Jureen P, Werngren J, Toro JC, Hoffner S (2008) Pyrazinamide resistance and pncA gene mutations in Mycobacterium tuberculosis. Antimicrobial agents Chemother 52(5):1852–1854Google Scholar
  26. Kandagal PB, Ashoka S, Seetharamappa J, Shaikh SM, Jadegoud Y, Ijare OB (2006) Study of the interaction of an anticancer drug with human and bovine serum albumin: spectroscopic approach. J Pharm Biomed Anal 41(2):393–399PubMedGoogle Scholar
  27. Katsuno K, Burrows JN, Duncan K, Van Huijsduijnen RH, Kaneko T, Kita K, Mowbray CE, Schmatz D, Warner P, Slingsby BT (2015) Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat Rev Drug Disco 14:751Google Scholar
  28. Kumar D, Beena, Khare G, Kidwai S, Tyagi AK, Singh R, Rawat DS (2014a) Synthesis of novel 1,2,3-triazole derivatives of isoniazid and their in vitro and in vivo antimycobacterial activity evaluation. Eur J Med Chem 81:301–313PubMedGoogle Scholar
  29. Kumar K, Pradines B, Madamet M, Amalvict R, Benoit N, Kumar V (2014b) 1H-1,2,3-triazole tethered isatin-ferrocene conjugates: synthesis and in vitro antimalarial evaluation. Eur J Med Chem 87:801–804PubMedGoogle Scholar
  30. Labadie GR, de la Iglesia A, Morbidoni HR (2011) Targeting tuberculosis through a small focused library of 1,2,3-triazoles. Mol Diversity 15(4):1017–1024Google Scholar
  31. Leroux FR, Manteau B, Vors J-P, Pazenok S (2008) Trifluoromethyl ethers–synthesis and properties of an unusual substituent. Beilstein J Org Chem 4:13–13PubMedPubMedCentralGoogle Scholar
  32. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25Google Scholar
  33. Machado D, Girardini M, Viveiros M, Pieroni M (2018) Challenging the drug-likeness dogma for new drug discovery in tuberculosis. Front Microbiol 9:1367PubMedPubMedCentralGoogle Scholar
  34. Mahata T, Kanungo A, Ganguly S, Modugula EK, Choudhury S, Pal SK, Basu G, Dutta S (2016) The benzyl moiety in a quinoxaline-based scaffold acts as a DNA intercalation switch. Angew Chem Int Ed Engl 55(27):7733–7736PubMedGoogle Scholar
  35. Manetsch R, Krasiński A, Radić Z, Raushel J, Taylor P, Sharpless KB, Kolb HC (2004) In situ click chemistry: enzyme inhibitors made to their own specifications. J Am Chem Soc 126(40):12809–12818PubMedGoogle Scholar
  36. Massarotti A, Aprile S, Mercalli V, Del Grosso E, Grosa G, Sorba G, Tron GC (2014) Are 1,4- and 1,5-disubstituted 1,2,3-triazoles good pharmacophoric groups? ChemMedChem 9(11):2497–2508PubMedGoogle Scholar
  37. Mohammed I, Kummetha IR, Singh G, Sharova N, Lichinchi G, Dang J, Stevenson M, Rana TM (2016) 1,2,3-triazoles as amide bioisosteres: discovery of a new class of potent HIV-1 Vif antagonists. J Med Chem 59:7677–7682PubMedPubMedCentralGoogle Scholar
  38. O’Hagan D (2008) Understanding organofluorine chemistry. An introduction to the C–F bond. Chem Soc Rev 37(2):308–319PubMedGoogle Scholar
  39. Ollinger J, Bailey MA, Moraski GC, Casey A, Florio S, Alling T, Miller MJ, Parish T (2013) A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis. PLOS ONE 8(4):e60531PubMedPubMedCentralGoogle Scholar
  40. Pop E, Oniciu DC, Pape ME, Cramer CT, Dasseux, J-LH. (2004) Lipophilicity parameters and biological activity in a series of compounds with potential cardiovascular applications. Croat Chem Acta 77:301–306Google Scholar
  41. Ran D, Wu X, Zheng J, Yang J, Zhou H, Zhang M, Tang Y (2007) Study on the interaction between florasulam and bovine serum albumin. J Fluoresc 17(6):721–726PubMedGoogle Scholar
  42. Rozwarski DA, Grant GA, Barton DH, Jacobs Jr. WR, Sacchettini JC (1998) Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Sciene 279(5347):98–102Google Scholar
  43. Sajja Y, Vanguru S, Vulupala HR, Nagarapu L, Perumal Y, Sriram D, Nanubolu JB (2017) Design, synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,3,4-oxadiazole derivatives. Chem Biol Drug Des 90:496–500PubMedGoogle Scholar
  44. Seetharamappa J, Kamat BP (2004) Spectroscopic studies on the mode of interaction of an anticancer drug with bovine serum albumin. Chem Pharm Bull 52(9):1053–1057PubMedGoogle Scholar
  45. Seifert M, Catanzaro D, Catanzaro A, Rodwell TC (2015) Genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis: a systematic review. PLOS ONE 10(3):e0119628–e0119628PubMedPubMedCentralGoogle Scholar
  46. Shafi S, Mahboob Alam M, Mulakayala N, Mulakayala C, Vanaja G, Kalle AM, Pallu R, Alam MS (2012) Synthesis of novel 2-mercapto benzothiazole and 1,2,3-triazole based bis-heterocycles: their anti-inflammatory and anti-nociceptive activities. Eur J Med Chem 49:324–333PubMedGoogle Scholar
  47. Shin J-A, Lim Y-G, Lee K-H (2012) Copper-catalyzed azide–alkyne cycloaddition reaction in water using cyclodextrin as a phase transfer catalyst. J Org Chem 77(8):4117–4122PubMedGoogle Scholar
  48. Singh A, Gut J, Rosenthal PJ, Kumar V (2017) 4-aminoquinoline-ferrocenyl-chalcone conjugates: synthesis and anti-plasmodial evaluation. Eur J Med Chem 125:269–277PubMedGoogle Scholar
  49. Soares de Melo C, Feng TS, van der Westhuyzen R, Gessner RK, Street LJ, Morgans GL, Warner DF, Moosa A, Naran K, Lawrence N et al. (2015) Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: structure activity relationships and ADME characterization. Bioorg Med Chem 23(22):7240–7250PubMedGoogle Scholar
  50. Speers AE, Adam GC, Cravatt BF (2003) Activity-based protein profiling in vivo using a copper(i)-catalyzed azide-alkyne [3 + 2] cycloaddition. J Am Chem Soc 125(16):4686–4687PubMedGoogle Scholar
  51. Suresh N, Nagesh HN, Renuka J, Rajput V, Sharma R, Khan IA, Kondapalli Venkata, Gowri CS (2014) Synthesis and evaluation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-(2-(4-substitutedpiperazin-1-yl)acetyl)piperazin-1-yl)quinoline-3-carboxylic acid derivatives as anti-tubercular and antibacterial agents. Eur J Med Chem 71:324–332PubMedGoogle Scholar
  52. Swetha Y, Reddy ER, Kumar JR, Trivedi R, Giribabu L, Sridhar B, Rathod B, Prakasham RS (2019) Synthesis, characterization and antimicrobial evaluation of ferrocene–oxime ether benzyl 1H-1,2,3-triazole hybrids. New J Chem 43(21):8341–8351Google Scholar
  53. Tahghighi A, Karimi S, Rafie Parhizgar A, Zakeri S (2018) Synthesis and antiplasmodial activity of novel phenanthroline derivatives: an in vivo study. Iran J Basic Med Sci 21(2):202–211PubMedPubMedCentralGoogle Scholar
  54. Tian J, Liu J, Zhang J, Hu Z, Chen X (2003) Fluorescence studies on the interactions of barbaloin with bovine serum albumin. Chem Pharm Bull 51(5):579–582PubMedGoogle Scholar
  55. Tornøe CW, Christensen C, Meldal M (2002) Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J Org Chem 67(9):3057–3064PubMedGoogle Scholar
  56. WHO (2016) WHO treatment guidelines for drug-resistant tuberculosis 2016 update. World Health Organization, Geneva, Switzerland.Google Scholar
  57. WHO (2018a) Infectious diseases. World Health Organization, Geneva, Switzerland. https://www.who.int/topics/infectious_diseases/en/. Accessed 2 Jul 2019
  58. WHO (2018b) Global TB Report 2018. World Health Organization, Geneva, Switzerland. https://www.who.int/tb/publications/global_report/en/. Accessed 4 Jul 2019
  59. Wilson CR, Gessner RK, Moosa A, Seldon R, Warner DF, Mizrahi V, Soares de Melo C, Simelane SB, Nchinda A, Abay E et al. (2017) Novel antitubercular 6-dialkylaminopyrimidine carboxamides from phenotypic whole-cell high throughput screening of a softfocus library: structure–activity relationship and target identification studies. J Med Chem 60(24):10118–10134PubMedPubMedCentralGoogle Scholar
  60. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D (2003) Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 167(11):1472–1477PubMedGoogle Scholar
  61. Zaw MT, Emran NA, Lin Z (2018) Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis. J Infect Public Health 11(5):605–610PubMedGoogle Scholar
  62. Zhang N-n, Liu Z-y, Liang J, Tang Y-x, Qian L, Gao Y-m, Zhang T-y, Yan M (2018) Design, synthesis, and biological evaluation of m-amidophenol derivatives as a new class of antitubercular agents. MedChemComm 9(8):1293–1304PubMedPubMedCentralGoogle Scholar
  63. Zhang S, Xu Z, Gao C, Ren Q-C, Chang L, Lv Z-S, Feng L-S (2017) Triazole derivatives and their anti-tubercular activity. Eur J Med Chem 138:501–513PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Pharmaceutical Chemistry, School of PharmacyNorth-West UniversityPotchefstroomSouth Africa
  2. 2.H3D Drug Discovery and Development CentrePotchefstroomSouth Africa
  3. 3.Centre of Excellence for Pharmaceutical SciencesNorth-West UniversityPotchefstroomSouth Africa
  4. 4.SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Division of Medical Microbiology, Department of PathologyUniversity of Cape TownCape TownSouth Africa
  5. 5.Institute of Infectious Disease and Molecular MedicineUniversity of Cape TownRondeboschSouth Africa
  6. 6.Wellcome Centre for Infectious Diseases Research in AfricaUniversity of Cape TownRondeboschSouth Africa

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