Medicinal Chemistry Research

, Volume 24, Issue 7, pp 2960–2971 | Cite as

Discovery of Rimonabant and its potential analogues as anti-TB drug candidates

  • J. M. GajbhiyeEmail author
  • N. A. More
  • Manoj D. Patil
  • R. Ummanni
  • S. S. Kotapalli
  • P. Yogeeswari
  • D. Sriram
  • V. H. Masand
Original Research


Rimonabant and its analogues have been synthesized in moderate to good yields using a simple synthetic route. All the newly synthesized compounds were subjected to in vitro screening against M. tuberculosis and M. smegmatis. The most potent analogue JMG-14 exhibits MIC value of 3.13 compared to 3.25 and 50 µg/ml for ethambutol and pyrazinamide, respectively. The molecular docking reveals that pyrazole ring, number and position of halogen atoms play a crucial role in deciding interactions with MTCYP-121. These findings open up a new avenue in the search of potent anti-TB drugs with rimonabant and its novel analogue JMG-14 as lead molecules.

Graphical Abstract


Rimonabant Diaryl pyrazoles Tuberculosis Mycobacterium tuberculosis H37Rv MTCYP-121 



JMG gratefully acknowledges CSIR-OSDD, CSIR-ORIGIN and DST-SERB, for the financial support.


  1. Abreu RM, Froufe HJ, Queiroz MJ, Ferreira IC (2012) Selective flexibility of side-chain residues improves VEGFR-2 docking score using AutoDock Vina. Chem Biol Drug Des 79(4):530–534PubMedCrossRefGoogle Scholar
  2. Belin P, Le Du MH, Fielding A, Lequin O, Jacquet M, Charbonnier JB, Lecoq A, Thai R, Courcon M, Masson C, Dugavet R, Pernodet JL, Gondry M (2009) Identification and structural basis of the reaction catalyzed by CYP121, an essential cytochrome P450 in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 106(18):7426–7431PubMedCentralPubMedCrossRefGoogle Scholar
  3. Chiang CY, Schaaf HS (2010) Management of drug-resistant tuberculosis. Int J Tuberc LungDis 14:672–682Google Scholar
  4. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C (2003) The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 163(9):1009–1021PubMedCrossRefGoogle Scholar
  5. Dumas VG, Defelipe LA, Petruk AA, Turjanski AG, Marti MA (2013) QM/MM study of the C–C coupling reaction mechanism of CYP121, an essential cytochrome p450 of mycobacterium tuberculosis. Proteins 82(6):1004–1021PubMedCrossRefGoogle Scholar
  6. Elzinga G, Raviglione MC, Maher D (2004) Scale up: meeting targets in global tuberculosis control. Lancet 363(9411):814–819PubMedCrossRefGoogle Scholar
  7. Handoko SD, Ouyang X, Su CT, Kwoh CK, Ong YS (2012) QuickVina: accelerating AutoDock Vina using gradient-based heuristics for global optimization. IEEE/ACM Trans Comput Biol Bioinform. 9(5):1266–1272PubMedCrossRefGoogle Scholar
  8. Hudson SA, McLean KJ, Surade S, Yang Y-Q, Leys D, Ciulli A, Munro AW, Abell C (2012) Application of fragment screening and merging to the discovery of inhibitors of the mycobacterium tuberculosis cytochrome P450 CYP121. Angew Chem Int Ed 51(37):9311–9316CrossRefGoogle Scholar
  9. Jagerovic N, Fernandez-Fernandez C, Goya P (2008) CB1 cannabinoid antagonists: structure-activity relationships and potential therapeutic applications. Curr Top Med Chem 8(3):205–230PubMedCrossRefGoogle Scholar
  10. Kang JG, Park CY (2012) Anti-obesity drugs: a review about their effects and safety. Diabetes Metab J 36(1):13–25PubMedCentralPubMedCrossRefGoogle Scholar
  11. Kotagiri VK, Suthrapu S, Mukunda Reddy J, Prasad Rao C, Bollugoddu V, Bhattacharya A, Bandichor R (2007) An improved synthesis of rimonabant: anti-obesity drug. Org Proc Res Dev 11:910–912CrossRefGoogle Scholar
  12. Kumar V, Kaur K, Gupta GK, Sharma AK (2013) Pyrazole containing natural products: synthetic preview and biological significance. Eur J Med Chem 69:735–753PubMedCrossRefGoogle Scholar
  13. Lan R, Liu Q, Fan P, Lin S, Fernando SR, McCallion D, Pertwee R, Makriyannis A (1999) Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42(4):769–776PubMedCrossRefGoogle Scholar
  14. Lange JH, Kruse CG (2005) Keynote review: medicinal chemistry strategies to CB1 cannabinoid receptor antagonists. Drug Discov Today 10(10):693–702PubMedCrossRefGoogle Scholar
  15. Masand VH, Jawarkar RD, Mahajan DT, Hadda TB, Sheikh J, Patil KN (2012) QSAR and CoMFA studies of biphenyl analogs of the anti-tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine(PA-824). Med Chem Res 21:2624–2629CrossRefGoogle Scholar
  16. Masand VH, Mahajan DT, Hadda TB, Jawarkar RD, Chavan H, Bandgar BP, Chauhan H (2013) Molecular docking and quantitative structure–activity relationship (QSAR) analyses of indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors. Med Chem Res 23(1):417–425CrossRefGoogle Scholar
  17. McLean KJ, Marshall KR, Richmond A, Hunter IS, Fowler K, Kieser T, Gurcha SS, Besra GS, Munro AW (2002) Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes. Microbiology 148:2937–2949PubMedGoogle Scholar
  18. Menozzi G, Merello L, Fossa P, Schenone S, Ranise A, Mosti L, Bondavalli F, Loddo R, Murgioni C, Mascia V, La Colla P, Tamburini E (2004) Synthesis, antimicrobial activity and molecular modeling studies of halogenated 4-[1H-imidazol-1-yl(phenyl)methyl]-1,5-diphenyl-1H-pyrazoles. Bioorg Med Chem 12(20):5465–5483PubMedCrossRefGoogle Scholar
  19. Moore AV, Kirk SM, Callister SM, Mazurek GH, Schell RF (1999) Safe determination of susceptibility of Mycobacterium tuberculosis to antimycobacterial agents by flow cytometry. J. Clin Microbio 37(3):479–483Google Scholar
  20. NCCLS-National Committee for Clinical Laboratory Standards (1995) Antimycobacterial susceptibility testing for Mycobacterium tuberculosis proposed standard M24-T. Villanova, PAGoogle Scholar
  21. Nunn P, Williams B, Floyd K, Dye C, Elzinga G, Raviglione M (2005) Tuberculosis control in the era of HIV. Nature Rev Immunol 5(10):819–826CrossRefGoogle Scholar
  22. Shukla D, Mesfin YM, Hailemariam D, Biadglign S, Kibret KT (2014) Association between HIV/AIDS and multi-drug resistance tuberculosis: a systematic review and meta-analysis. PLoS ONE 9(1):e82235CrossRefGoogle Scholar
  23. Stigliani JL, Bernardes-Genisson V, Bernadou J, Pratviel G (2012) Cross-docking study on InhA inhibitors: a combination of Autodock Vina and PM6-DH2 simulations to retrieve bio-active conformations. Org Bio-Mol Chem 10(31):6341–6349CrossRefGoogle Scholar
  24. Sundaramurthi JC, Kumar S, Silambuchelvi K, Hanna LE (2011) Molecular docking of azole drugs and their analogs on CYP121 of mycobacterium tuberculosis. Bioinformation 7(3):130–133PubMedCentralPubMedCrossRefGoogle Scholar
  25. Tiwari A, Saxena S, Pant AB, Srivastava P (2012) Protein-ligand interaction studies of retinol-binding protein 3 with herbal molecules using AutoDock for the management of Eales’ disease. J Ocul Biol Dis Infor 5(2):40–43PubMedCentralPubMedCrossRefGoogle Scholar
  26., Global Tuberculosis Report 2013, in, 2013
  27., Tuberculosis prevalence surveys: a handbook, in, 2011

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • J. M. Gajbhiye
    • 1
    Email author
  • N. A. More
    • 1
  • Manoj D. Patil
    • 1
  • R. Ummanni
    • 2
  • S. S. Kotapalli
    • 2
  • P. Yogeeswari
    • 3
  • D. Sriram
    • 3
  • V. H. Masand
    • 4
  1. 1.Division of Organic ChemistryCSIR-National Chemical LaboratoryPuneIndia
  2. 2.Centre for Chemical BiologyIndian Institute of Chemical TechnologyHyderabadIndia
  3. 3.Tuberculosis Drug Discovery Laboratory, Pharmacy GroupBirla Institute of Technology and Science, PilaniHyderabadIndia
  4. 4.Department of ChemistryVidyaBharati CollegeAmravatiIndia

Personalised recommendations