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Medicinal Chemistry Research

, Volume 26, Issue 11, pp 2889–2899 | Cite as

Synthesis, antimycobacterial screening and molecular docking studies of 4-aryl-4′-methyl-2′-aryl-2,5′-bisthiazole derivatives

  • Yogita K. Abhale
  • Abhijit D. Shinde
  • Keshav K. Deshmukh
  • Laxman Nawale
  • Dhiman Sarkar
  • Prafulla B. Choudhari
  • Santosh S. Kumbhar
  • Pravin C. Mhaske
Original Research

Abstract

A series of 4-aryl-4′-methyl-2′-aryl-2,5′-bisthiazole derivatives (5ao) were synthesized and screened for inhibitory activity against Mycobacterium tuberculosis H37Ra (ATCC 25177) and Mycobacterium bovis BCG (ATCC 35743) strains. Five lead compounds (5e, 5f, 5g, 5h, and 5o) were further confirmed from their dose dependent effect against MTB and Bovine–Calmette–Guerin. The most promising compounds 5f (MIC90: 11.32 µg/mL), 5h (MIC90: 11.59 µg/mL), and 5o (MIC90: 23.64 µg/mL) showed strong antitubercular activity against dormant MTB and BCG as well as almost insignificant cytotoxicity up to 100 µg/mL against HeLa, A549, and PANC-1 human cancer cell lines. Further, the synthesized compounds were found to have potential antibacterial activity against Gram-negative bacteria, Escherichia coli, Pseudomonas flurescence and Gram-positive bacteria, Staphylococcus aureus, Bacillus subtilis. Most of the synthesized compounds showed moderate activity against fungal strain Candida albicans. Molecular docking studies of these compounds showed significant interactions with crystal structure of the cytochrome P45014α-sterol demethylase (CYP51) PDB ID: 1E9X. Hydrogen bond interactions with SER261 and VAL395 are important interactions for selective inhibition of designed inhibitors. Compounds 5f, 5h, and 5o showed significant interactions with 1E9X. All the experimental results promote us to consider this series as a starting point for the development of novel, selective and more potent antitubercular agents in the future.

Keywords

Bisthiazoles Mycobacterium tuberculosis Antimicrobial activity Cytotoxicity Docking study 

Notes

Acknowledgements

YKA expresses her gratefulness to CSIR [File No. 08/590(0001)/2012-EMR-I] for the financial support. PCM would like to thank University Grant Commission (UGC No. 42-355(SR)/2013), New Delhi, India for the financial assistance and CSIR-NCL, Pune for supporting biological activity. Central Analysis facility, Savitribai Phule Pune University, Pune is also acknowledged for spectral analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1988_MOESM1_ESM.docx (635 kb)
Supplementary Information

References

  1. Abhale YK, Deshmukh KK, Sasane AV, Chavan AP, Mhaske PC (2016) Fused heterocycles: synthesis and antitubercular activity of novel 6-substituted-2-(4-methyl-2-substituted phenylthiazol-5-yl)Himidazo[1,2-a]pyridine. J Heterocycl Chem 53:229–233CrossRefGoogle Scholar
  2. Abhale YK, Sasane AV, Chavan AP, Deshmukh KK, Kotapalli SS, Ummanni R, Sayyad SF, Mhaske PC (2015) Synthesis and biological screening of 2′-aryl/benzyl-2-aryl-4-methyl-4′,5-bithiazolyls as possible anti-tubercular and antimicrobial agents. Eur J Med Chem 94:340–347CrossRefPubMedGoogle Scholar
  3. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48(3):589–601PubMedGoogle Scholar
  4. Alvarez G, Martinez J, Varela J, Birriel E, Cruces E, Gabay M, Leal SM, Escobar P, Aguirre-Lopez B, Cabrera N, Tuena de Gomez-Puyou M, Gomez PA, Perez-Montfort R, Yaluff G, Torres S, Serna E, Vera de Bilbao N, Gonzalez M, Cerecetto H (2015) Development of bis-thiazoles as inhibitors of triosephosphate isomerase from Trypanosoma cruzi. Identification of new non-mutagenic agents that are active in vivo. Eur J Med Chem 100:246–256CrossRefPubMedGoogle Scholar
  5. Araniciu C, Marutescu L, Oniga S, Oniga O, Chifiriuc MC, Palage M (2014a) Evaluation of the antimicrobial and anti-biofilm activity of some 4,2 and 5,2 bisthiazoles derivatives. Dig J Nanomater Biostruct 9:123–131Google Scholar
  6. Araniciu C, Parvu A, Palage M, Oniga S, Benedec D, Oniga I, Oniga O (2014b) The effect of some 4,2 and 5,2 bisthiazole derivatives on nitro-oxidative stress and phagocytosis in acute experimental inflammation. Molecules 19:9240–9256CrossRefPubMedGoogle Scholar
  7. Araniciu C, Parvu AE, Tiperciuc B, Palage M, Oniga S, Verite P, Oniga O (2013) Synthesis and evaluation of the anti-inflammatory activity of some 2-(trimethoxyphenyl)-4-R1-5-R2-thiazoles. Dig J Nanomater Bios 8:699–709Google Scholar
  8. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, O’Brien RJ, Reves RR, Reichman LB, Simone PM, Starke JR, Vernon AA (2003) American thoracic society/centers for disease control and prevention/infectious diseases society of america: treatment of tuberculosis. Am J Respir Crit Care Med 167(4):603–662CrossRefPubMedGoogle Scholar
  9. Chen F, Chai H, Su MB, Zhang YM, Li J, Xie X, Nan FJ (2014) Potent and orally efficacious bisthiazole-based histone deacetylase inhibitors. ACS Med Chem Lett 5(6):628–633CrossRefPubMedPubMedCentralGoogle Scholar
  10. Choudhari PB, Bhatia MS (2012) 3D QSAR, docking studies, and pharmacophore modeling of selected factor Xa inhibitors. Med Chem Res 21:1427–1432CrossRefGoogle Scholar
  11. Ciapetti G, Cenni E, Pratelli L, Pizzoferrato A (1993) In vitro evaluation of cell/ biomaterial interaction by MTT assay. Biomaterials 14(5):359–364CrossRefPubMedGoogle Scholar
  12. Gaikwad ND, Patil SV, Bobade VD (2012) Synthesis and biological evaluation of some novel thiazole substituted benzotriazole derivatives. Bioorg Med Chem Lett 22:3449–3454CrossRefPubMedGoogle Scholar
  13. Hartkoorn RC, Chandler B, Owen A, Ward SA, Bertel Squire S, Back DJ, Khoo SH (2007) Differential drug susceptibility of intracellular and extracellular tuberculosis, and the impact of P-glycoprotein. Tuberculosis 87(3):248–255CrossRefPubMedGoogle Scholar
  14. Inamdar GS, Pandya AN, Thakar HM, Sudarsanam V, Kachler S, Sabbadin D, Moro S, Klotz KN, Vasu KK (2013) New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides. Eur J Med Chem 63:924–934CrossRefPubMedGoogle Scholar
  15. Johnson M, Antonio T, Reith ME, Dutta AK (2012) Structure–activity relationship study of N6-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine analogs: development of highly selective D3 dopamine receptor agonists along with a highly potent D2/D3 agonist and their pharmacological characterization. J Med Chem 55:5826–5840CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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 73:62–68CrossRefPubMedGoogle Scholar
  17. Khan A, Sarkar S, Sarkar D (2008) Bactericidal activity of 2-nitroimidazole against the active replicating stage of Mycobacterium bovis BCG and Mycobacterium tuberculosis with intracellular efficacy in THP-1 macrophages. Int J Antimicrob Agents 32(1):40–45CrossRefPubMedGoogle Scholar
  18. Kuete V (2010) Potential of Cameroonian plants and derived products against microbial infections: a review. Planta Med 76(14):1479–1491CrossRefPubMedGoogle Scholar
  19. Lee YS, Kim H, Kim YH, Roh EJ, Han H, Shin KJ (2012) Synthesis and structure–activity relationships of tri-substituted thiazoles as RAGE antagonists for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 22(24):7555–7561CrossRefPubMedGoogle Scholar
  20. Leelabai MS, Dinesh AS, Abbs F, Kallikat RN (2008) Synthesis of novel 1,4-bis[(5-aroyl-2-N,N-disubstituted amino)thiazol-4-yl]benzenes. ARKIVOC 15:288–296Google Scholar
  21. Loo TW, Bartlett MC, Clarke DM (2013) Bithiazole correctors rescue CFTR mutants by two different mechanisms. Biochemistry 52(31):5161–5163CrossRefPubMedPubMedCentralGoogle Scholar
  22. Malik S, Bahare RS, Khan SA (2013) Design, synthesis and anticonvulsant evaluation of N-(benzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamide derivatives: a hybrid pharmacophore approach. Eur J Med Chem 67:1–13CrossRefPubMedGoogle Scholar
  23. Mishra CB, Kumari S, Tiwari M (2015) Thiazole: a promising heterocycle for the development of potent CNS active agents. Eur J Med Chem 92:1–34CrossRefPubMedGoogle Scholar
  24. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1-2):55–63CrossRefPubMedPubMedCentralGoogle Scholar
  25. Navale A, Pawar S, Deodhar M, Kale A (2013) Synthesis of substituted benzo[d]thiazol-2-ylcarbamates as potential anticonvulsants. Med Chem Res 22(9):4316–4321CrossRefGoogle Scholar
  26. Patravale AA, Gore AH, Kolekar GB, Deshmukh MB, Choudhari PB, Bhatia MS, Prabhu S, Jamdhade MD, Patole MS, Anbhule PV (2016) Synthesis, biological evaluation and molecular docking studies of some novel indenospiro derivatives as anticancer agents. J Taiwan Inst Chem Eng 68:105–118CrossRefGoogle Scholar
  27. Sarkar S, Sarkar D (2012) Potential use of nitrate reductase as a biomarker for the identification of active and dormant inhibitors of Mycobacterium tuberculosis in a THP1 infection model. J Biomol Screen 17(7):966–973CrossRefPubMedGoogle Scholar
  28. Shelke SH, Mhaske PC, Hande P, Bobade VD (2013) Synthesis and antimicrobial activities of novel series of 1-((4-methyl-2-substituted thiazol-5-yl)methyleneam INO)-2-substituted isothiourea derivatives. Phosphorus Sulfur Silicon Relat Elem 188:1262–1270CrossRefGoogle Scholar
  29. Siddiqui N, Ahsan W (2010) Triazole incorporated thiazoles as a new class of anticonvulsants: design, synthesis and in vivo screening. Eur J Med Chem 45(4):1536–1543CrossRefPubMedGoogle Scholar
  30. Singh R, Nawale LU, Arkile M, Shedbalkar U, Wadhwani S, Sarkar D, Chopade B (2015) Chemical and biological metal nanoparticles as antimycobacterial agents: a comparative study. Int J Antimicrob Agents 46(2):183–188CrossRefPubMedGoogle Scholar
  31. Singh U, Akhtar S, Mishra A, Sarkar D (2011) A novel screening method based on menadione mediated rapid reduction of tetrazolium salt for testing of anti-mycobacterial agents. J Microbiol Methods 84:202–207CrossRefPubMedGoogle Scholar
  32. Tomasic T, Katsamakas S, Hodnik Z, Ilas J, Brvar M, Solmajer T, Montalvao S, Tammela P, Banjanac M, Ergovic G, Anderluh M, Masic LP, Kikelj D (2015) Discovery of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles as novel DNA gyrase inhibitors targeting the ATP-binding site. J Med Chem 58:5501–5521CrossRefPubMedGoogle Scholar
  33. Urbanek RA, Xiong H, Wu Y, Blackwell W, Steelman G, Rosamond J, Wesolowski SS, Campbell JB, Zhang M, Brockel B, Widzowski DV (2013) Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists. Bioorg Med Chem Lett 23(2):543–547CrossRefPubMedGoogle Scholar
  34. WHO Tuberculosis Fact Sheet (2016) http://www.who.int/mediacentre/factsheets/fs104/en/Google Scholar
  35. Zignol M, Hosseini MS, Wright A (2006) Global incidence of multidrug-resistant tuberculosis. J Infect Dis 194(4):s479–s485CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Yogita K. Abhale
    • 1
  • Abhijit D. Shinde
    • 2
  • Keshav K. Deshmukh
    • 1
  • Laxman Nawale
    • 3
  • Dhiman Sarkar
    • 3
  • Prafulla B. Choudhari
    • 4
  • Santosh S. Kumbhar
    • 4
  • Pravin C. Mhaske
    • 2
  1. 1.Post-Graduate Department of Chemistry and Research Centre, S. N. Arts, D. J. M. Commerce and B. N. S. Science CollegeSavitribai Phule Pune UniversitySangamnerIndia
  2. 2.Post Graduate Department of Chemistry, S. P. Mandali’s Sir Parashurambhau CollegeSavitribai Phule Pune UniversityPuneIndia
  3. 3.CombiChemBio Resource Centre, CSIR-National Chemical LaboratoryPuneIndia
  4. 4.Department of Pharmaceutical ChemistryBharati Vidyapeeth College of PharmacyKolhapurIndia

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