Advertisement

Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents

  • Ashutosh Prasad Tiwari
  • B. Sridhar
  • Helena I. Boshoff
  • Kriti Arora
  • G. Gautham Shenoy
  • K. E. Vandana
  • G. Varadaraj BhatEmail author
Original Article

Abstract

Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4–7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development.

Graphic abstract

Keywords

TB Diphenylether InhA Molecular docking Correlation study Antitubercular 

Notes

Acknowledgements

The authors are thankful to Manipal Academy of Higher Education and Manipal College of Pharmaceutical Sciences for providing necessary supports and facilities to carry out the present research work. Authors are thankful to D’IICT and National Mol Bank (NMB) facility of CSIR-IICT, Hyderabad, India, for the help in biological evaluation of compounds. Authors also thank Manipal-Schrödinger Centre for molecular simulations. This work was funded in part by the Intramural Research Program of the NIH, NIAID.

Compliance with ethical standards

Conflict of interest

The authors confirm that this article content has no conflict of interest.

Supplementary material

11030_2019_9990_MOESM1_ESM.docx (1015 kb)
Supplementary material 1 (DOCX 1015 kb)
11030_2019_9990_MOESM2_ESM.docx (1.8 mb)
Supplementary material 2 (DOCX 1871 kb)

References

  1. 1.
    WHO (2018) Tuberculosis (TB). WHO, GenevaGoogle Scholar
  2. 2.
    World Health Organization (2018) BCG vaccine: WHO position paper, February 2018 – Recommendations. Vaccine 73–96.  https://doi.org/10.1016/j.vaccine.2018.03.009
  3. 3.
    WHO (2017) Guidelines for treatment of drug-susceptible tuberculosis and patient care. WHO, GenevaGoogle Scholar
  4. 4.
    Rožman K, Sosič I, Fernandez R, Young RJ, Mendoza A, Gobec S, Encinas L (2017) A new ‘golden age’ for the antitubercular target InhA. Drug Discov Today 22(3):492–502CrossRefGoogle Scholar
  5. 5.
    Forrellad MA, Klepp LI, Gioffré A et al (2013) Virulence factors of the Mycobacterium tuberculosis complex. Virulence.  https://doi.org/10.4161/viru.22329 Google Scholar
  6. 6.
    Zhang Y, Heym B, Allen B et al (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature.  https://doi.org/10.1038/358591a0 Google Scholar
  7. 7.
    Narang A, Giri A, Gupta S et al (2017) Contribution of putative efflux pump genes to isoniazid resistance in clinical isolates of Mycobacterium tuberculosis. Int J Mycobacteriol 6:177.  https://doi.org/10.4103/ijmy.ijmy_26_17 CrossRefGoogle Scholar
  8. 8.
    McMurry LM, Oethinger M, Levy SB (1998) Triclosan targets lipid synthesis. Nature 394:531–532CrossRefGoogle Scholar
  9. 9.
    Parikh SL, Xiao G, Tonge PJ (2000) Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Biochemistry 39:7645–7650.  https://doi.org/10.1021/bi0008940 CrossRefGoogle Scholar
  10. 10.
    Sullivan TJ, Truglio JJ, Boyne ME et al (2006) High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem Biol.  https://doi.org/10.1021/cb0500042 Google Scholar
  11. 11.
    Pan P, Knudson SE, Bommineni GR et al (2014) Time-dependent diaryl ether inhibitors of InhA: structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy. ChemMedChem.  https://doi.org/10.1002/cmdc.201300429 Google Scholar
  12. 12.
    am Ende CW, Knudson SE, Liu N et al (2008) Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. Bioorganic Med Chem Lett 18:3029–3033.  https://doi.org/10.1016/j.bmcl.2008.04.038 CrossRefGoogle Scholar
  13. 13.
    Luckner SR, Liu N, Am Ende CW et al (2010) A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. J Biol Chem.  https://doi.org/10.1074/jbc.M109.090373 Google Scholar
  14. 14.
    Stewart MJ, Parikh S, Xiao G et al (1999) Structural basis and mechanism of enoyl reductase inhibition by triclosan. J Mol Biol.  https://doi.org/10.1006/jmbi.1999.2907 Google Scholar
  15. 15.
    Freundlich JS, Wang F, Vilchèze C et al (2009) Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. ChemMedChem 4:241–248.  https://doi.org/10.1002/cmdc.200800261 CrossRefGoogle Scholar
  16. 16.
    Chollet A, Maveyraud L, Lherbet C, Bernardes-Génisson V (2018) An overview on crystal structures of InhA protein: apo-form, in complex with its natural ligands and inhibitors. Eur J Med Chem 146:318–343.  https://doi.org/10.1016/j.ejmech.2018.01.047 CrossRefGoogle Scholar
  17. 17.
    Cappel D, Sherman W, Beuming T (2017) Calculating water thermodynamics in the binding site of proteins—applications of WaterMap to drug discovery. Curr Top Med Chem.  https://doi.org/10.2174/1568026617666170414141452 Google Scholar
  18. 18.
    Cheraïti N, Brik ME (1999) Synthesis of a new triprotonated ligand and selective O-demethylation of methyl aryl ether by boron tribromide. Tetrahedron Lett 40:4327–4330.  https://doi.org/10.1016/S0040-4039(99)00786-8 CrossRefGoogle Scholar
  19. 19.
    Bhagat S, Sharma R, Sawant DM, Sharma L, Chakraborti AK (2006) LiOH · H2O as a novel dual activation catalyst for highly efficient and easy synthesis of 1, 3-diaryl-2-propenones by Claisen—Schmidt condensation under mild conditions. J Mol Catal A: Chem 244(1–2):20–24.  https://doi.org/10.1016/j.molcata.2005.08.039 CrossRefGoogle Scholar
  20. 20.
    Wei E, Liu B, Lin S, Liang F (2014) Multicomponent reaction of chalcones, malononitrile and DMF leading to γ-ketoamides. Org Biomol Chem 12:6389–6392.  https://doi.org/10.1039/c4ob00971a CrossRefGoogle Scholar
  21. 21.
    Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1(4):337–341CrossRefGoogle Scholar
  22. 22.
    Kar SS, Bhat VG, Shenoy VP et al (2018) Design, synthesis and evaluation of novel diphenyl ether derivatives against drug susceptible and resistant strains of Mycobacterium tuberculosis. Chem Biol Drug Des.  https://doi.org/10.1111/cbdd.13379 Google Scholar
  23. 23.
    Khan A, Sarkar D (2008) A simple whole cell based high throughput screening protocol using Mycobacterium bovis BCG for inhibitors against dormant and active tubercle bacilli. J Microbiol Methods.  https://doi.org/10.1016/j.mimet.2008.01.015 Google Scholar
  24. 24.
    Barot KP, Jain SV, Gupta N et al (2014) Design, synthesis and docking studies of some novel (R)-2-(4′- chlorophenyl)-3-(4′-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5] imidazo [1,2-c]pyrimidin-4-ol derivatives as antitubercular agents. Eur J Med Chem 83:245–255.  https://doi.org/10.1016/j.ejmech.2014.06.019 CrossRefGoogle Scholar
  25. 25.
    Kaniga K, Cirillo DM, Hoffner S et al (2016) A multilaboratory, multicountry study to determine MIC quality control ranges for phenotypic drug susceptibility testing of selected First-Line Antituberculosis Drugs, Second-Line Injectables, Fluoroquinolones, Clofazimine, and Linezolid. J Clin Microbiol.  https://doi.org/10.1128/JCM.01138-16 Google Scholar
  26. 26.
    Candice SDM, Feng TS, Van Der Westhuyzen R et al (2015) Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: structure activity relationships and ADME characterization. Bioorganic Med Chem 23:7240–7250.  https://doi.org/10.1016/j.bmc.2015.10.021 CrossRefGoogle Scholar
  27. 27.
    Kumar V, Sobhia ME (2014) Insights into the bonding pattern for characterizing the open and closed state of the substrate-binding loop in Mycobacterium tuberculosis InhA. Future Med Chem.  https://doi.org/10.4155/fmc.14.27 Google Scholar
  28. 28.
    Pan P, Tonge J, Tonge P (2012) Targeting InhA, the FASII enoyl-ACP reductase: SAR studies on novel inhibitor scaffolds. Curr Top Med Chem 12:672–693.  https://doi.org/10.2174/156802612799984535 CrossRefGoogle Scholar
  29. 29.
    Sherman W, Day T, Jacobson MP et al (2006) Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem 49:534–553.  https://doi.org/10.1021/jm050540c CrossRefGoogle Scholar
  30. 30.
    Robinson D, Bertrand T, Carry JC et al (2016) Differential water thermodynamics determine PI3 K-beta/delta selectivity for solvent-exposed ligand modifications. J Chem Inf Model 56:886–894.  https://doi.org/10.1021/acs.jcim.5b00641 CrossRefGoogle Scholar
  31. 31.
    Solutions BAX BRUKER ADVANCED X-RAY SOLUTIONS SMART APEX User’s Manual, https://www.ndsu.edu/chemistry/files/mcl/smart5_UserManual.pdf
  32. 32.
    Sheldrick GM (2015) Crystal structure refinement with SHELXL. Acta Crystallogr Sect C 71:3–8.  https://doi.org/10.1107/S2053229614024218 CrossRefGoogle Scholar
  33. 33.
    Spek AL (2015) PLATON SQUEEZE: a tool for the calculation of the disordered solvent contribution to the calculated structure factors. Acta Crystallogr Sect C Struct Chem.  https://doi.org/10.1107/S2053229614024929 Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalIndia
  2. 2.X-ray Crystallography DivisionCSIR – Indian Institute of Chemical TechnologyHyderabadIndia
  3. 3.Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaUSA
  4. 4.Department of Microbiology, Kasturba Medical CollegeManipal Academy of Higher EducationManipalIndia

Personalised recommendations