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Antibacterial evaluation and molecular docking studies of pyrazole–thiosemicarbazones and their pyrazole–thiazolidinone conjugates

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Abstract

A library of pyrazole–thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier–Haack reaction. The compounds were tested for anti-microbial activity against two Gram-positive bacteria (Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) and four Gram-negative bacteria (Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa). Among the compounds tested, 3-((2,4-dichlorophenyl)-1-(2,4-dinitrophenyl)-1H-pyrazol-yl)methylene)hydrazinecarbothioamide (3a) and 2-((3-(2-chlorophenyl)-1-(2,4 dinitrophenyl)-1H-pyrazol-4-yl)methyleneamino)thiazolidin-4-one (4b) emerged as the most potent anti-microbial compounds with minimum bactericidal concentrations of < 0.2 µM against MRSA and S. aureus. Structure–activity relationship analysis further revealed that the presence of 2,4-dichloro moiety surprisingly influenced the activity of the compounds. Molecular docking studies of the compounds into the crystal structure of topoisomerase II and topoisomerase IV suggest that compounds 3a and 4b preferably interact with the targets through hydrogen bonding.

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References

  1. Tsogoeva SB (2010) Recent progress in the development of synthetic hybrids of natural or unnatural bioactive compounds for medicinal chemistry. Mini Rev Med Chem 10(9):773–793

    CAS  PubMed  Google Scholar 

  2. Bhosle MR, Mali JR, Pal S, Srivastava AK, Mane RA (2014) Synthesis and antihyperglycemic evaluation of new 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids having pyrazolyl pharmacophores. Bioorg Med Chem Lett 24(12):2651–2654

    CAS  PubMed  Google Scholar 

  3. Helal M, Salem M, El-Gaby M, Aljahdali M (2013) Synthesis and biological evaluation of some novel thiazole compounds as potential anti-inflammatory agents. Eur J Med Chem 65:517–526

    CAS  PubMed  Google Scholar 

  4. Tsuruoka A, Kaku Y, Kakinuma H, Tsukada I, Yanagisawa M, Nara K, Naito T (1998) Synthesis and antifungal activity of novel thiazole-containing triazole antifungals. II. Optically active ER-30346 and its derivatives. Chem Pharm Bull 46(4):623–630

    CAS  Google Scholar 

  5. Storer R, Ashton CJ, Baxter AD, Hann MM, Marr CL, Mason AM, Mo C-L, Myers PL, Noble SA, Penn CR (1999) The synthesis and antiviral activity of 4-fluoro-1-β-d-ribofuranosyl-1H-pyrazole-3-carboxamide. Nucleosides Nucleotides Nucleic Acids 18(2):203–216

    CAS  Google Scholar 

  6. Khunt R, Khedkar V, Chawda R, Chauhan N, Parikh A, Coutinho E (2012) Synthesis, antitubercular evaluation and 3D-QSAR study of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazole derivatives. Bioorg Med Chem Lett 22(1):666–678

    CAS  PubMed  Google Scholar 

  7. Singh P, Mothilal S, Kerru N, Singh-Pillay A, Gummidi L, Erukainure OL, Islam MS (2019) Comparative α-glucosidase and α-amylase inhibition studies of rhodanine–pyrazole conjugates and their simple rhodanine analogues. Med Chem Res 28(2):143–159

    CAS  Google Scholar 

  8. Wu Y, Huang YP, Zhou SC, Tan YQ, Xu BG, Liang Z, Deng XQ (2018) Synthesis of 1, 3-diaryl pyrazole derivatives and evaluation of anticonvulsant and antimicrobial activities. Lat Am J Pharm 37(5):1017–1027

    Google Scholar 

  9. Sen S, De B, Easwari TS (2014) Synthesized 2-substituted-3-phenylthiazolidine-4-ones as potent antioxidants and antidiabetic agents. Trop J Pharm Res 13(9):1445–1454

    CAS  Google Scholar 

  10. Christiansen RG, Bell MR, D’Ambra TE, Mallamo JP, Herrmann JL, Ackerman JH, Opalka CJ, Kullnig RK, Winneker RC, Snyder BW (1990) Antiandrogenic steroidal sulfonylpyrazoles. J Med Chem 33(8):2094–2100

    CAS  PubMed  Google Scholar 

  11. Thangamani S, Younis W, Seleem MN (2015) Repurposing celecoxib as a topical antimicrobial agent. Front Microbiol 6(6):750

    PubMed  PubMed Central  Google Scholar 

  12. Bekhit AA, Fahmy HT, Rostom SA, Baraka AM (2003) Design and synthesis of some substituted 1H-pyrazolyl-thiazolo [4, 5-d] pyrimidines as anti-inflammatory–antimicrobial agents. Eur J Med Chem 38(1):27–36

    CAS  PubMed  Google Scholar 

  13. Ottana R, Maccari R, Barreca ML, Bruno G, Rotondo A, Rossi A, Chiricosta G, Di Paola R, Sautebin L, Cuzzocrea S (2005) 5-Arylidene-2-imino-4-thiazolidinones: design and synthesis of novel anti-inflammatory agents. Bioorg Med Chem 13(13):4243–4252

    CAS  PubMed  Google Scholar 

  14. Omar K, Geronikaki A, Zoumpoulakis P, Camoutsis C, Soković M, Ćirić A, Glamočlija J (2010) Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs. Bioorg Med Chem 18(1):426–432

    CAS  PubMed  Google Scholar 

  15. Mistry BM, Jauhari S (2013) Synthesis and in vitro antimicrobial and anti-tubercular evaluation of some quinoline-based azitidinone and thiazolidinone analogues. Med Chem Res 22(2):635–646

    CAS  Google Scholar 

  16. Hrib NJ, Jurcak JG, Bregna DE, Dunn RW, Geyer HM III, Hartman HB, Roehr JE, Rogers KL, Rush DK (1992) 3 [4-[1-(6-Fluorobenzo [b] thiophen-3-yl)-4-piperazinyl] butyl]-2, 5, 5-trimethyl-4-thiazolidinone: a new atypical antipsychotic agent for the treatment of schizophrenia. J Med Chem 35(14):2712–2715

    CAS  PubMed  Google Scholar 

  17. Cai WX, Liu AL, Li ZM, Dong WL, Liu XH, Sun NB (2016) Synthesis and anticancer activity of novel thiazole-5-carboxamide derivatives. Appl Sci 6(1):8

    Google Scholar 

  18. Hambley TW (1997) The influence of structure on the activity and toxicity of Pt anti-cancer drugs. Coord Chem Rev 166:181–223

    CAS  Google Scholar 

  19. Gomha SM, Abdallah MA, Abbas IM, Kazem MS (2018) Synthesis, cytotoxicity evaluation, molecular docking and utility of novel chalcones as precursors for heterocycles incorporating pyrazole moiety. Med Chem 14(4):344–355

    CAS  PubMed  Google Scholar 

  20. Ibrahim D (2009) Synthesis and biological evaluation of 3, 6-disubstituted [1, 2, 4] triazolo [3, 4-b][1, 3, 4] thiadiazole derivatives as a novel class of potential anti-tumor agents. Eur J Med Chem 44(7):2776–2781

    CAS  PubMed  Google Scholar 

  21. Abdallah M, Gomha S, Abbas I, Kazem M, Alterary S, Mabkhot Y (2017) An efficient synthesis of novel pyrazole-based heterocycles as potential antitumor agents. Appl Sci 7(8):785

    Google Scholar 

  22. Abdel-Wahab BF, Mohamed SF, Amr AE-GE, Abdalla MM (2008) Synthesis and reactions of thiosemicarbazides, triazoles, and Schiff bases as antihypertensive α-blocking agents. Chem Mon 139(9):1083–1090

    CAS  Google Scholar 

  23. Bell SC, Wei P (1976) Syntheses of heterocylic fused thiazole acetic acids. 2. J Med Chem 19(4):524–530

    CAS  PubMed  Google Scholar 

  24. Siddiqui N, Ahsan W (2011) Synthesis, anticonvulsant and toxicity screening of thiazolyl–thiadiazole derivatives. Med Chem Res 20(2):261–268

    CAS  Google Scholar 

  25. Bilbao-Ramos P, Galiana-Roselló C, Dea-Ayuela MA, González-Alvarez M, Vega C, Rolón M, Pérez-Serrano J, Bolás-Fernández F, González-Rosende ME (2012) Nuclease activity and ultrastructural effects of new sulfonamides with anti-leishmanial and trypanocidal activities. Parasitol Int 61(4):604–613

    CAS  PubMed  Google Scholar 

  26. Badorc A, Bordes M-F, de Cointet P, Savi P, Bernat A, Lalé A, Petitou M, Maffrand J-P, Herbert J-M (1997) New orally active non-peptide fibrinogen receptor (GpIIb-IIIa) antagonists: identification of ethyl 3-[N-[4-[4-[amino [(ethoxycarbonyl) imino] methyl] phenyl]-1, 3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl) methyl] piperid-4-yl] amino] propionate (SR 121787) as a potent and long-acting antithrombotic agent. J Med Chem 40(21):3393–3401

    CAS  PubMed  Google Scholar 

  27. Küçükgüzel ŞG, Oruç EE, Rollas S, Şahin F, Özbek A (2002) Synthesis, characterisation and biological activity of novel 4-thiazolidinones, 1, 3, 4-oxadiazoles and some related compounds. Eur J Med Chem 37(3):197–206

    PubMed  Google Scholar 

  28. Küçükgüzel G, Kocatepe A, De Clercq E, Şahin F, Güllüce M (2006) Synthesis and biological activity of 4-thiazolidinones, thiosemicarbazides derived from diflunisal hydrazide. Eur J Med Chem 41(3):353–359

    PubMed  Google Scholar 

  29. Franklin TJ, Snow GA (2005) Biochemistry and molecular biology of antimicrobial drug action. Springer, Cham

    Google Scholar 

  30. Tocher JH (1997) Reductive activation of nitroheterocyclic compounds. Gener Pharmacol Vasc Syst 28(4):485–487

    CAS  Google Scholar 

  31. Liang B, Cheng H-Y, Kong D-Y, Gao S-H, Sun F, Cui D, Kong F-Y, Zhou A-J, Liu W-Z, Ren N-Q (2013) Accelerated reduction of chlorinated nitroaromatic antibiotic chloramphenicol by biocathode. Environ Sci Technol 47(10):5353–5361

    CAS  PubMed  Google Scholar 

  32. Viegas-Junior C, Danuello A, da Silva Bolzani V, Barreiro EJ, Fraga CAM (2007) Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem 14(17):1829–1852

    CAS  PubMed  Google Scholar 

  33. Reece RJ, Maxwell A (1991) DNA gyrase: structure and function. Crit Rev Biochem Mol Biol 26(3–4):335–375

    CAS  PubMed  Google Scholar 

  34. Collin F, Karkare S, Maxwell A (2011) Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl Microbiol Biotechnol 92(3):479–497

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Maxwell A (1997) DNA gyrase as a drug target. Trends Microbiol 5(3):102–109

    CAS  PubMed  Google Scholar 

  36. Yusufzai SK, Osman H, Khan MS, Razik BMA, Ezzat MO, Mohamad S, Sulaiman O, Gansau JA, Parumasivam TJCCJ (2018) 4-Thiazolidinone coumarin derivatives as two-component NS2B/NS3 DENV flavivirus serine protease inhibitors: synthesis, molecular docking, biological evaluation and structure–activity relationship studies. Chem Cent J 12(1):69

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Dudek EP, Dudek GO (1967) Proton magnetic resonance spectra of thiocarboxamides. J Org Chem 32(3):823–824

    CAS  Google Scholar 

  38. Denis OR-V (2010) Hector; Struelens, Marc J: The problem of resistance. In: Finch Roger G (ed) Antibiotic and chemotherapy. Elsevier, Amsterdam, pp 24–48

    Google Scholar 

  39. Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Iwai N, Hiyama Y, Suzuki K, Ito H, Terauchi H, Kawasaki M (2004) Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives. J Med Chem 47(14):3693–3696

    CAS  PubMed  Google Scholar 

  40. Bennion BJ, Be NA, McNerney MW, Lao V, Carlson EM, Valdez CA, Malfatti MA, Enright HA, Nguyen TH, Lightstone FC (2017) Predicting a drug’s membrane permeability: a computational model validated with in vitro permeability assay data. J Phys Chem B 121(20):5228–5237

    CAS  PubMed  Google Scholar 

  41. Alegaon SG, Hirpara M, Alagawadi K, Hullatti K, Kashniyal K (2014) Synthesis of novel pyrazole–thiadiazole hybrid as potential potent and selective cyclooxygenase-2 (COX-2) inhibitors. Bioorg Med Chem Lett 24(22):5324–5329

    CAS  PubMed  Google Scholar 

  42. http://www.rcsb.org/pdb/home/home.do

  43. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612

    CAS  PubMed  Google Scholar 

  44. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M (2015) PLIP: fully automated protein–ligand interaction profiler. Nucleic Acids Res 43(W1):W443–W447

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

NK thanks the National Research Foundation South Africa for a Competitive Grant for Rated Researchers (Grant No. 118534) and Incentive Funding for Rated Researchers (Grant No. 114817). We would also like to thank the Centre for High Performance Computing based in Cape Town for access to computational resources.

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  1. School of Chemistry, University of KwaZulu-Natal, Westville Campus, Private Bag X54001, Durban, 4000, South Africa

    Oluwakemi Ebenezer, Ashona Singh-Pillay, Neil A. Koorbanally & Parvesh Singh

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  1. Oluwakemi Ebenezer
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  2. Ashona Singh-Pillay
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  3. Neil A. Koorbanally
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  4. Parvesh Singh
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Correspondence to Neil A. Koorbanally or Parvesh Singh.

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Ebenezer, O., Singh-Pillay, A., Koorbanally, N.A. et al. Antibacterial evaluation and molecular docking studies of pyrazole–thiosemicarbazones and their pyrazole–thiazolidinone conjugates. Mol Divers 25, 191–204 (2021). https://doi.org/10.1007/s11030-020-10046-w

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