Medicinal Chemistry Research

, Volume 27, Issue 2, pp 546–559 | Cite as

Design, synthesis, molecular modeling, and ADMET studies of some pyrazoline derivatives as shikimate kinase inhibitors

  • Jainey P. James
  • K. Ishwar Bhat
  • Uttam A. More
  • Shrinivas D. Joshi
Original Research


A series of pyrazoline derivatives were synthesized and their structures have been characterized by IR, 1H NMR, 13C NMR, mass spectral and elemental analysis. The novel compounds were designed as Mycobacterium tuberculosis shikimate kinase (MtSK) inhibitors based on docking studies using Sybyl-X 2.0 software. In silico ADMET predictions revealed that all compounds had minimal toxic effects and had good absorption as well as solubility characteristics. Thus these compounds may serve as potential lead compound for developing new anti-tubercular drug.Among the tested compounds 4c, 5b, and 6a exhibited promising antitubercular activity. Additional, some compounds were also evaluated for their cytotoxic activity against EAC cell lines using the tryphan blue exclusion method.


Pyrazolines Antitubercular activity Mycobacterium tuberculosis Shikimate Kinase 



The authors are thankful to Nitte University, Mangalore for the financial support. Also acknowledge NGSM Institute of Pharmaceutical Sciences, Mangalore for providing the facilities. We also thank Maratha Mandal Dental College, Belguam for providing facilities for antitubercular activity tests. Director, SAIF, Indian Institute of Science, Bangalore, India, and Director, CSRI, Lucknow, India for NMR and mass spectral analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Agarwal NA, Soni PA (2005) Reaction of 2’-hydroxy-5’-acetamido chalcones with dimethyl sulfoxide-iodine, pyridine-mercuric(II) acetate and triethanolamine. Indian J Chem 44B:2601–2603Google Scholar
  2. Azarifar D, Maleki B (2005) Silica-supported synthesis of some 1,3,5-trisubstituted 2-pyrazolines under solvent-free and microwave irradiation conditions. J Heterocycl Chem 42:157–159CrossRefGoogle Scholar
  3. Bandodkar BS, Schmitt S (2007) Pyrazolonederivates, processes for preparing them, pharmaceutical compositions containing them, and their use as inhibitors of the MtSK (Mycobacterium tuberculosisshikimate kinase) enzyme. Patent: WO/ 2007/020426 A1Google Scholar
  4. Bandodkar SB, Schmitt S (2010) Pyrazoline derivative forthe treatment of tuberculosis.United States Patent Application Publication(ASTRAZENECA R&D BOSTON) Pub. No:0179161A1Google Scholar
  5. Bano S, Javed K, Ahmad S, Rathish IG, Singh S, Alam MS (2011) Synthesis and biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide moiety as potential anti-inflammatory and anti-cancer agent. Eur J Med Chem 46:5763–5768CrossRefPubMedGoogle Scholar
  6. Blanco B, Prado V, Lence E, Otero JM, Garcia-Doval C, Raaij MJ et al. (2013) Mycobacterium tuberculosis Shikimate kinase inhibitors: Design and simulation studies of the catalytic turnover. J Am ChemSoc 135(33):12366–12376CrossRefGoogle Scholar
  7. Cohen NC (1996) Guidebook on Molecular Modelling in Drug Design. Academic Press, San DiegoGoogle Scholar
  8. Collins LA, Franzblau SG (1997) Microplatealamar blue assay versus bactec 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother 41:1004–1009PubMedPubMedCentralGoogle Scholar
  9. Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G et al. (2012) admetSAR: a comprehensive source and free tool for evaluating chemical ADMET properties. J ChemInf Model 52:3099–3105CrossRefGoogle Scholar
  10. Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, Hernandez A et al. (1998) Rapid, low-technology MIC determination with clinical mycobacterium tuberculosis isolates by using the microplatealamar blue assay. J Clin Microbiol 36:362–366PubMedPubMedCentralGoogle Scholar
  11. Garrat DC (1964) The quantitative analysis of drugs. Chapman and Hall, JapanCrossRefGoogle Scholar
  12. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity – a rapid access to atomic charges. Tetrahedron 36:3219–3228CrossRefGoogle Scholar
  13. Ghorab MM, Osman AN, Noaman E et al. (2006) The utility of isothiocyanatothiophenes in the synthesis of thieno[2,3-d]pyrimidine derivatives as possible radioprotective and anticancer agents. Phosphorus Sulfur Silicon Relat Elem 181:1983–1996CrossRefGoogle Scholar
  14. Gu Y, Reshetnikova L, Li Y, Wu Y, Yan H, Singh S, Ji X (2002) Crystal structure of shikimate kinase from Mycobacterium tuberculosis reveals the dynamic role of the LID domain in catalysis. J Mol Biol 319(3):779–789CrossRefPubMedGoogle Scholar
  15. Holla BS, Mahalinga M, Poojary B, Ashok M, Akberali PM (2006) Synthesis of Pyrazolines Promoted by Amberlyst-15 Catalyst. Indian J Chem 45B:568–571Google Scholar
  16. Insuasty B, Garcia A, Quiroga J, Abonia R, Ortiz A, Nogueras M et al. (2011) Efficient microwave-assisted synthesis and antitumor activity of novel 4,4’-methylenebis[2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols]. Eur J Med Chem 46:2436–2440CrossRefPubMedGoogle Scholar
  17. Jain AN (1996) Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities. J Comput Aided Mol Des 10:427–440CrossRefPubMedGoogle Scholar
  18. Jain AN (2003) Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J Med Chem 46:499–511CrossRefPubMedGoogle Scholar
  19. Joshi SD, Dixit SR, Kirankumar MN, Aminabhavi TM, Raju KVSN, Narayan R et al. (2016) Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. Eur J Med Chem 107:133–152CrossRefPubMedGoogle Scholar
  20. Khalil OM (2012) Synthesis and anti-inflammatory activity of 1- acetyl/propanoyl-5-aryl-3-(4-morpholinophenyl)-4,5-dihydro-1H-pyrazole derivatives. Med Chem Res 21:3240–3245CrossRefGoogle Scholar
  21. Khunt RC, Khedkar VM, Chawda RS, Chauhan NA, Parikh AR, Coutinho EC (2012) Synthesis, antitubercular evaluation and 3D-QSAR study of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazole derivatives. Bioorg Med Chem Lett 22:666–678CrossRefPubMedGoogle Scholar
  22. Kumar A, Bhat G, Varadaraj BG, Rajeev K, Singla RK (2013) Synthesis and evaluation of antioxidant activity ofnovel3,5-disubstituted-2-pyrazolines. Bull Fac Pharm Cairo Univ 51:167–173CrossRefGoogle Scholar
  23. Kumar D, Kumar NM, Akamatsu K, Kusaka E, Harada H, Ito T (2010) Synthesis and biological evaluation of indolylchalcones as antitumor agents. Bioorg Med Chem Lett 20:3916–3919CrossRefPubMedGoogle Scholar
  24. Manna K, Agrawal YK (2009) Microwave assisted synthesis of new indophenazine 1,3,5-trisubstruted pyrazoline derivatives of benzofuran and their antimicrobial activity. Bioorg Med Chem Lett 19:2688–2692CrossRefPubMedGoogle Scholar
  25. Manna KK, Agrawal YK (2011) Potent in vitro and in vivo antitubercular activity of certain newly synthesized indophenazine 1,3,5-trisubstituted pyrazoline derivatives bearing benzofuran. Med Chem Res 20:300–306CrossRefGoogle Scholar
  26. Manojkumar P, Ravi TK, Subbuchettiar G (2009) Synthesis of coumarin heterocyclic derivatives with antioxidant activity and in vitro cytotoxic activity against tumour cells. Acta Pharm 59:159–170CrossRefPubMedGoogle Scholar
  27. Marcocci PL, Sckaki A, Albert GM (1994) Antioxidant action of Ginkgo biloba extracts EGP761. Method Enzymol 234:462–475CrossRefGoogle Scholar
  28. Mistry BD, Desai KR, Patel JA, Patel NI (2012) Conventional and microwave assisted synthesis of pyrazole derivatives and screening of their antibacterial and antifungal activities. Ind J Chem 51:746–751Google Scholar
  29. Monga V, Goyal K, Steindel M, Malhotra M, Rajani DP, Rajani SD (2014) Synthesis and evaluation of new chalcones, derived pyrazoline and cyclohexenone derivatives as potent antimicrobial, antitubercular and antileishmanial agents. Med Chem Res 23:2019–2032CrossRefGoogle Scholar
  30. Nitin NA, Soni PA (2007) Synthesis of pyrazole and isoxazole in triethanolamine medium. Ind J Chem 46B:532–534Google Scholar
  31. Parmar SS, Pandey BR, Dwivedi C, Harbison RD (2006) Anticonvulsant activity and monoamine oxidase inhibitory properties of 1,3,5-trisubstituted pyrazolines. J Pharm Sci 63:1152–1155CrossRefGoogle Scholar
  32. Pereira JH, Vasconcelos IB, Oliveira JS, Caceres RA, Azevedo WF, Basso LA, Santos DS (2007) Shikimate kinase: a potential target for development of novel antitubercularagents. Curr Drug Targets 8:459–468CrossRefPubMedGoogle Scholar
  33. Shandala MY, Hamdy AM (2008) Synthesis of Some New Substituted 1,3,5-Triaryl Pyrazolines. Nat J Chem 30:338–342Google Scholar
  34. Soni N, Pande K, Kalsi R, Gupta TK, Parmar SS, Barthwal JP (1987) Inhibition of rat brain monoamineoxidase and succinic dehydrogenase by anticonvulsant pyrazolines. Res Commun Cement Pathol Pharm 56:129–132Google Scholar
  35. Sreejayan N, Rao MNA (1996) Free radical scavenging activity by curcuminoids. Drug Res 46:169–171Google Scholar
  36. Swaminathan S (2002) Basic concepts in the treatment of tuberculosis. Indian J Pediatr 69:44–49Google Scholar
  37. Taj T, Kamble RR, Gireesh TM, Hunnur RK, Margankop SB (2011) One-pot synthesis of pyrazoline derivatised carbazoles as antitubercular, anticancer agents, their DNA cleavage and antioxidant activities. Eur J Med Chem 46:4366–4373CrossRefPubMedGoogle Scholar
  38. Tripos International. (2012) Sybyl-X 2.0, Tripos International, St. Louis, MO, USAGoogle Scholar
  39. Wermuth CG (1996) The Practice of Medicinal Chemistry. Academic Press, San DiegoGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryNGSM Institute of Pharmaceutical Sciences, Nitte UniversityMangaloreIndia
  2. 2.Department of Pharmaceutical ChemistryNovel Drug Design and Discovery Laboratory, S.E.T’s College of PharmacyDharwadIndia

Personalised recommendations