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POM analyses and evaluation of in vitro antimicrobial, antitumor activity of 4H-pyrimido[2,1-b]benzothiazole derivatives

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Abstract

A facile, efficient, and convenient synthesis of 4H-pyrimido[2,1-b]benzothiazole derivatives is described using aromatic aldehydes, ethyl acetoacetate, and 2-amino benzothiazole in the presence of l-proline under solvent-free conditions. Present methodology has advantages such as short reaction time, no side products, and easy to work up. Synthesized library compounds have been evaluated for their antitumor and antimicrobial activity. Further, we have compared the experimental work with theoretical parameters using molecular property analysis to develop new ideas about the preparation of pyrimido benzothiazole derivatives for their possible application against cancer and chronic microbial diseases. It has been concluded that Petra/osiris/molinspiration (POM) analyses might prove to be a suitable method to correlate the structural features of 4H-pyrimido[2,1-b]benzothiazole derivatives with their promising combined antimicrobial/antitumor activity and may contribute to the development of novel antimicrobial and antitumor agents against drug resistance.

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References

  • Alaimo RJ (1973) The synthesis of some 4H-pyrimido[2,1-b]benzothiazol 4-ones. J Heterocycl Chem 10:769–772

    Article  CAS  Google Scholar 

  • Alcaide B, Almendros P, Luna A, Torres MR (2006) Proline-catalyzed diastereoselective direct Aldol reaction between 4-oxoazetidine-2-carbaldehydes and ketones. J Org Chem 71:4818–4822

    Article  CAS  PubMed  Google Scholar 

  • Alemán J, Cabrera S (2013) Applications of asymmetric organocatalysis in medicinal chemistry. Chem Soc Rev 42:774–793

    Article  PubMed  Google Scholar 

  • Asundaria ST, Patel KC (2012) Synthesis, characterization and antimicrobial activity of thiazole, benzothiazole and pyrimidine derivatives bearing sydnone moieties. Pharm Chem J 45:725–731

    Article  CAS  Google Scholar 

  • Bartovic A, Ilavski D, Simo D, Zalibera L, Belicová A, Seman M (1995) Synthesis of nitro-substituted 4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxylic acids and their spectral characteristics. Collect Czech Chem Commun 60:583–593

    Article  CAS  Google Scholar 

  • Bogevig A, Kumaragurubaran N, Juhl K, Zhuang W, Jorgensen KA (2002) Direct organo-catalytic asymmetric α-amination of aldehydes—a simple approach to optically active α-amino aldehydes, α-amino alcohols, and α-amino acids. Angew Chem Int Ed 41:1790–1793

    Article  CAS  Google Scholar 

  • Chowdari NS, Ramachary DB, Barbas CF (2003) Organocatalysis in ionic liquids: highly efficient l-proline-catalyzed direct asymmetric mannich reactions involving ketone and aldehyde nucleophiles. Synlett 12:1906–1909

    Google Scholar 

  • Cordova A, Notz W, Barbas CF (2002) Direct organocatalytic aldol reactions in buffered aqueous media. Chem Commun 24:3024–3025

    Article  Google Scholar 

  • Doma A, Kulkarni R, Garlapati A, Krishna PR (2014) Synthesis and anti-inflammatory activity of novel pyrimidino benzothiazole amine derivatives. Pharmacophore 5:331–342

    Google Scholar 

  • El-Sherbeny MA (2000) Synthesis of certain pyrimido[2,1-b]benzothiazole and benzothiazolo[2,3-b]quinazoline derivatives for in vitro antitumor and antiviral activities. Arzneimittelforschung 50:848–853

    CAS  PubMed  Google Scholar 

  • Franchini C, Muraglia M, Corbo F, Florio MA, Di Mola A, Rosato A, Matucci R, Nesi M, Bambeke FV, Vitali C (2009) Synthesis and biological evaluation of 2-mercapto-1,3-benzothiazole derivatives with potential antimicrobial activity. Arch Der Pharmazie 342:605–613

    Article  CAS  Google Scholar 

  • Gupta A, Rawat S (2010) Synthesis and cyclization of benzothiazole: review. J Curr Pharm Res 3:13–23

    Google Scholar 

  • Ha S, Koh T, Ong S, Lee T, Sivasothy Y (2009) Synthesis of 2-(4-propyloxyphenyl) benzothiaozle. Molbank M609:1–3

    Google Scholar 

  • Hadda TB, Fathi J, Chafchaouni I, Masand V, Charrouf Z, Chohan ZH, Jawarkar R, Fergoug T (2013) Computational POM and 3D-QSAR evaluation of experimental in vitro HIV-1 integrase inhibition of amide-containing di-ketoacids. Med Chem Res 22:1456–1464

    Article  CAS  Google Scholar 

  • Heilmann J, Wasescha MR, Schmidt TJ (2001) The influence of glutathione and cysteine levels on the cytotoxicity of helenanolide type sesquiterpene lactones against KB cells. Bioorg Med Chem 9:2189–2194

    Article  CAS  PubMed  Google Scholar 

  • Janey JM, Hsiao Y, Armstrong JD (2006) Proline-catalyzed, asymmetric mannich reactions in the synthesis of a DPP-IV inhibitor. J Org Chem 71:390–392

    Article  CAS  PubMed  Google Scholar 

  • Kralisch D, Stark A, Korsten S, Kreisel G, Ondruschka B (2005) Energetic, enviromental and economic balances: spice up your ionic liquid research efficiency. Green Chem 7:301–309

    Article  CAS  Google Scholar 

  • Kumar A, Maurya RA (2007) Synthesis of polyhydroquinoline derivatives through unsymmetric Hantzsch reaction using organocatalysts. Tetrahedron 63:1946–1952

    Article  CAS  Google Scholar 

  • Kutyrev A, Kappe T (1999) Methanetricarboxylates as key reagents for the simple preparation of heteroaryl carboxamides with potential biological activity. J Heterocycl Chem 36:237–240

    Article  CAS  Google Scholar 

  • Lal J, Sharma M, Gupta S, Parashar P, Sahu P, Agarwal DD (2012) Hydrotalcite: a novel and reusable solid catalyst for one-pot synthesis of 3,4-dihydropyrimidinones and mechanistic study under solvent free conditions. J Mol Catal A Chem 352:31–37

    Article  CAS  Google Scholar 

  • Landreau C, Deniaud D, Evain M, Reliquet A (2002) Efficient regioselective synthesis of triheterocyclic compounds: imidazo[2,1-b]benzothiazoles, pyrimido[2,1-b]-benzothiazolones and pyrimido[2,1-b]benzothiazoles. J Chem Soc Perkin Trans 1:741–745

    Article  Google Scholar 

  • List B, Lerner RA, Barbas CF III (2000) Proline-catalyzed direct asymmetric Aldol reactions. J Am Chem Soc 122:2395

    Article  CAS  Google Scholar 

  • Matzke M, Stolte S, Thiele K, Juffernholz T, Arning J, Ranke J, Welzbiermann U, Jastorff B (2007) The influence of anion species on the toxicity of 1-alkyl-3-methylimidazolium ionic liquids observed in an (eco) toxicological test battery. Green Chem 9:1198–1207

    Article  CAS  Google Scholar 

  • Mosman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  Google Scholar 

  • Ozcelik B, Sheikh J, Orhan I, Juneja H, Bennani B, Kerbal A, Cavalcanti SMT, Leite ACL, Hadda TB (2013) Outstanding effect of the conformational restriction of isoquinolines: hints for the development of optimized antimicrobial agents. Res Chem Intermed 39:2955–2962

    Article  CAS  Google Scholar 

  • Parvez A, Meshram J, Tiwari V, Sheikh J, Dongre R, Youssoufi MH, Hadda TB (2010a) Pharmacophores modeling in terms of prediction of theoretical physicochemical properties and verification by experimental correlations of novel coumarin derivatives produced via Betti’s protocol. Eur J Med Chem 45:4370–4378

    Article  CAS  PubMed  Google Scholar 

  • Parvez A, Jyotsna M, Youssoufi MH, Hadda TB (2010b) Theoretical calculations and experimental verification of the antibacterial potential of some monocyclic beta-lactames containing two synergetic buried antibacterial pharmacophore sites. Phosphorus Sulfur Silicon Relat Elem 185:1500–1510

    Article  CAS  Google Scholar 

  • Pham T, Cho C, Yun Y (2010) Environmental fate and toxicity of ionic liquids: a review. Water Res 44:352–372

    Article  CAS  PubMed  Google Scholar 

  • Ramachary DB, Chowdari NS, Barbas CF III (2003) Organocatalytic asymmetric domino Knoevenagel/Diels–Alder reactions: a bioorganic approach to the diastereospecific and enantioselective construction of highly substituted spiro[5,5]undecane-1,5,9-triones. Angew Chem 115:4365–4369

    Article  Google Scholar 

  • Rao GBD, Acharya BN, Verma SK, Kaushik MP (2011) N,N′-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent for the synthesis of pyrimidone and pyrimidine derivatives via Biginelli reaction. Tetrahedron Lett 52:809–812

    Article  CAS  Google Scholar 

  • Rasalkar MS, Potdar MK, Mohile SS, Salunkhe MM (2005) An ionic liquid influenced l-proline catalysed asymmetric Michael addition of ketones to nitrostyrene. J Mol Catal A Chem 235:267–270

    Article  CAS  Google Scholar 

  • Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C (1999) Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med 26:1231–1237

    Article  CAS  PubMed  Google Scholar 

  • Romani D, Brandán SA (2015) Structural and spectroscopic studies of two 1,3-benzothiazole tautomers with potential antimicrobial activity in different media. Prediction of their reactivities. Comp Theor Chem 1061:89–99

    Article  CAS  Google Scholar 

  • Roy PJ, Landry K, Leblanc Y (1997) Condensation of 2-amino-5-chlorobenzoxazole with α-bromoketones: a mechanistic study. Heterocycles 45:2239–2246

    Article  CAS  Google Scholar 

  • Sahu PK, Sahu PK, Lal J, Thavaselvam D, Agarwal DD (2012a) A facile green synthesis and in vitro antimicrobial activity 4H-pyrimido[2,1-b][1,3]benzothiazole derivatives using aluminum trichloride under solvent free conditions. Med Chem Res 21:3826–3834

    Article  CAS  Google Scholar 

  • Sahu PK, Sahu PK, Gupta SK, Thavaselvam D, Agarwal DD (2012b) Synthesis and evaluation of antimicrobial activity of 4H-pyrimido[2,1-b]benzothiazole, pyrazole and benzylidene derivatives of curcumin. Eur J Med Chem 54:366–378

    Article  CAS  PubMed  Google Scholar 

  • Sahu PK, Sahu PK, Gupta SK, Agarwal DD (2013) Role of calcinations and basicity of hydrotalcite as catalyst for environmental benign novel synthesis of 4H-pyrimido[2,1-b][1,3]benzothiazole derivatives of curcumin. Catal Sci Technol 3:1520–1530

    Article  CAS  Google Scholar 

  • Shaabani A, Rahmati A, Naderi S (2005) A novel one-pot three-component reaction: synthesis of triheterocyclic 4H-pyrimido[2,1-b]benzazoles ring systems. Bioorg Med Chem Lett 15:5553–5557

    Article  CAS  PubMed  Google Scholar 

  • Silva ALR, Cimas A, Ribeiro da Silva MDMC (2014) Energetic study of benzothiazole and two methylbenzothiazole derivatives: calorimetric and computational approaches. J Chem Thermodyn 73:3–11

    Article  CAS  Google Scholar 

  • Singh MK, Tilak R, Nath G, Awasthi SK, Agarwal A (2013) Design, synthesis and antimicrobial activity of novel benzothiazole analogs. Eur J Med Chem 63:635–644

    Article  CAS  PubMed  Google Scholar 

  • Tanabe Y, Kawai A, Yoshida Y, Ogure M, Okumura H (1997) Preparation of fused thiadiazolo and imidazobenzothiazoles from 2-aminobenzothiazoles. Their fungicidal activity. Heterocycles 45:1579–1588

    Article  CAS  Google Scholar 

  • Trapani G, Carotti A, Franco A, Latrofa G, Gench G, Liso G (1993) Structure-affinity relationships of some alkoxycarbonyl-2H- or -4H-pyrimido[2,1-b]benzothia-zol-2- or 4-one benzodiazepine receptor ligands. Eur J Med Chem 28:13–21

    Article  CAS  Google Scholar 

  • Trapani G, Franco A, Latrofa G, Carotti A, Genchi G, Serra M, Biggioand G, Liso G (1996) Synthesis and benzodiazepine receptor binding of some imidazo- and pyrimido[2,1-b]benzothiazoles. Eur J Med Chem 31:575–587

    Article  CAS  Google Scholar 

  • Wade JJ, Tose CB, Matson CJ, Stelzer VL (1983) Synthesis and antiallergic activity of some acidic derivatives of 4H-pyrimido[2,1-b]benzazol-4-ones. J Med Chem 26:608–611

    Article  CAS  PubMed  Google Scholar 

  • Yadav JS, Kumar SP, Kondaji G, Rao RS, Nagaiah K (2004) A novel l-proline catalyzed Biginelli reaction: one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions. Chem Lett 33:1168–1169

    Article  CAS  Google Scholar 

  • Yevich JP, Temple DL, Covington RR, Owens DA, Seidehameland RJ, Dungan KW (1982) Antiallergics: 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]ben-zothiazol-4-ones. J Med Chem 25:864–868

    Article  CAS  PubMed  Google Scholar 

  • Yoshida M, Hayakawa I, Hayashi N, Agatsuma T, Oda Y, Tanzawa F, Iwasaki S, Koyama K, Furukawa H, Kurakata S, Sugano Y (2005) Synthesis and biological evaluation of benzothiazole derivatives as potent antitumor agents. Bioorg Med Chem Lett 15:3328–3332

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to express their sincere thanks to SAIF Punjab University Chandigarh for their spectral analysis.

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Authors and Affiliations

  1. School of Studies in Chemistry, Jiwaji University, Gwalior, Madhya Pradesh, 474011, India

    Pramod K. Sahu & Dau D. Agarwal

  2. Department of Industrial Chemistry, Jiwaji University, Gwalior, Madhya Pradesh, 474011, India

    Pramod K. Sahu, Praveen K. Sahu & Dau D. Agarwal

  3. Synthetic Organic Chemistry Laboratory, Department of Chemistry, Dr. H.S. Gour University (A Central University), Sagar, MP, 470003, India

    Pushkal Samadhiya

  4. Indian Pharmacopoeia Commission Ministry of Health and Family Welfare, Sector-23, Raj Nagar, Ghaziabad, 201002, India

    Puran L. Sahu

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  1. Pramod K. Sahu
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  2. Praveen K. Sahu
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  3. Pushkal Samadhiya
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  4. Puran L. Sahu
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Correspondence to Pramod K. Sahu.

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Sahu, P.K., Sahu, P.K., Samadhiya, P. et al. POM analyses and evaluation of in vitro antimicrobial, antitumor activity of 4H-pyrimido[2,1-b]benzothiazole derivatives. Med Chem Res 25, 1551–1563 (2016). https://doi.org/10.1007/s00044-016-1589-8

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