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Synthesis, biological evaluation and QSAR study of a series of substituted quinazolines as antimicrobial agents

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Abstract

A novel series of 1-N-substituted-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea derivatives (6a–6r) and 1-N-substituted-3-(7-(4-methylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea derivatives (14a–14s) were synthesized and screened for antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli. Biological results indicated that the synthesized compounds showed a broad-spectrum activity against tested microorganisms at MIC values between 6.25 and 100 μg/mL. Compound 6r showed a broad spectrum of activity and was found to be active against all tested species. A quantitative structure–activity relationship study has been carried out on the synthesized compounds to get better insights into pharmacophoric features responsible for the antibacterial activity. Genetic function approximation technique was used to identify descriptors that influence biological activity. Hydrophobic (AlogP98), electronic (atomic polarizability), and topological (radius of gyration) descriptors were found to affect the activity significantly. Generated model was found to be statistically significant (r 2 = 0.86, predictive index = 0.96) and predictive as indicated by very low residuals in internal and external cross-validation.

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References

  • Abbanat D, Macielag M, Bush K (2003) Novel antibacterial agents for the treatment of serious Gram-positive infections. Expert Opin Investig Drugs 12:379–399

    Article  PubMed  CAS  Google Scholar 

  • Alenxandre FR, Berecibar A, Besson T (2003) Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations. Tetrahedron 59:1413–1419

    Article  Google Scholar 

  • Bedi PMS, Kumar V, Mahajan MP (2004) Synthesis and biological activity of novel antibacterial quinazolines. Bioorg Med Chem Lett 14:5211–5213

    Article  PubMed  CAS  Google Scholar 

  • Bozdogan BÜ, Esel D, Whitener C, Browne FA, Appelbaum PC (2003) Antibacterial susceptibility of a vancomycin-resistant Staphylococcus aureus strain isolated at the Hershey Medical Center. J Antimicrob Chemother 52:864–868

    Article  PubMed  CAS  Google Scholar 

  • Dalhoff A (1994) Quinolone resistance in Pseudomonas aeruginosa and Staphylococcus aureus. Development during therapy and clinical significance. Infection 22:S111–S121

    Article  PubMed  Google Scholar 

  • Ertan T, Yildiz I, Tekiner-Gulbas B, Bolelli K, Temiz-Arpaci O, Ozkan S, Yalcin I, Aki E (2009) Synthesis, biological evaluation and 2D-QSAR analysis of benzoxazoles as antimicrobial agents. Eur J Med Chem 44:501–510

    Article  PubMed  CAS  Google Scholar 

  • Fan YL, Shi M, Kohn KW, Pommier Y, Weinstein JN (2001) Quantitative structure–antitumor activity relationships of camptothecin analogs: cluster analysis and genetic algorithm-based studies. J Med Chem 44:3254–3263

    Article  PubMed  CAS  Google Scholar 

  • Ghose AK, Viswanadhan VN, Wendolowski JJ (1998) Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: an analysis of ALOGP and CLOGP methods. J Phys Chem A 102:3762–3772

    Article  CAS  Google Scholar 

  • Gineinah MM, El-Sherbeny MA, Nasr MN, Maarouf AR (2002) Synthesis and antiinflammatory screening of some quinazoline and quinazolyl-4-oxoquinazoline derivatives. Arch Pharm 335:556–562

    Article  CAS  Google Scholar 

  • Hansch C, Fujita T (1964) p-σ–π Analysis. A method for the correlation of biological activity and chemical structure. J Am Chem Soc 86:1616–1626

    Article  CAS  Google Scholar 

  • Hopfinger AJ, Rogers D (1994) Application of genetic function approximation to quantitative structure–activity relationships and quantitative structure–property relationships. J Chem Inf Comput Sci 34(4):845–866

    Article  Google Scholar 

  • Jantova S, Stankovsky S, Spirkova K (2004) In vitro antibacterial activity of ten series of substituted quinazolines. Biologia Bratislava 59:741–752

    CAS  Google Scholar 

  • Karki RG, Kulkarni VM (2001) Three-dimensional quantitative structure–activity relationship (3D-QSAR) of 3-aryloxazolidin-2-one antibacterials. Bioorg Med Chem 9:3153–3160

    Article  PubMed  CAS  Google Scholar 

  • Khan IA, Koul JL, Koul S, Kumar A, Nargotra A, Qazi GN, Sharma S, Taneja SC, Thota N (2009) Quantitative structure–activity relationship (QSAR) of aryl alkenyl amides/imines for bacterial efflux pump inhibitors. Eur J Med Chem 44:229–238

    Article  PubMed  Google Scholar 

  • Knesl P, Röseling D, Jordis U (2006) Improved synthesis of substituted 6,7-dihydroxy-4-quinazolineamines: tandutinib, erlotinib and gefitinib. Molecule 11:286–297

    Article  CAS  Google Scholar 

  • Livermore DM (2000) Antibiotic resistance in staphylococci. Int J Antimicrob Agents 16:S3–S10

    Article  PubMed  CAS  Google Scholar 

  • Mosaad SM, Mohammed KI, Ahmed MA, Abdel-Hamide SG (2004) Synthesis of certain new 6-iodoquinazolines as potential antitubercular agents. J Appl Sci 4:302–307

    Article  Google Scholar 

  • National Committee for Clinical Laboratory Standards (NCCLS) (1982) Standard methods for dilution of antimicrobial susceptibility test for bacteria which grow aerobically. National Committee for Clinical Laboratory Standards, Villanova, p 242

    Google Scholar 

  • Pearlman DA, Charifson PS (2001) Are free energy calculations useful in practice? A comparison with rapid scoring functions for the p38 MAP kinase protein system. J Med Chem 44:3417–3423

    Article  PubMed  CAS  Google Scholar 

  • Peterangelo S, Seybold P (2004) Synergistic interactions among QSAR descriptors. Int J Quantum Chem 96:1–9

    Article  CAS  Google Scholar 

  • Poole K (2001) Multidrug resistance in Gram-negative bacteria. Curr Opin Microbiol 4:500–508

    Article  PubMed  CAS  Google Scholar 

  • Poole K (2004) Efflux-mediated multiresistance in Gram-negative bacteria. Clin Microbiol Infect 10:12–26

    Article  PubMed  CAS  Google Scholar 

  • Rosowsky A, Papoulis AT, Forsch RA, Queener SF (1999) Synthesis and antiparasitic and antitumor activity of 2,4-diamino-6-(arylmethyl)-5,6,7,8-tetrahydroquinazoline analogs of piritrexim. J Med Chem 42:1007–1017

    Article  PubMed  CAS  Google Scholar 

  • Roy P, Roy K (2007) On some aspects of variable selection for partial least squares regression models. QSAR Combi Sci 27:302–313

    Article  Google Scholar 

  • Sharma MC, Sahu NK, Kohli DV, Chaturvedi SC, Sharma S (2009) Synthesis, characterization and biological activities of some 1-(nicotilamino)-2-substituted-azetidine-4-ones as potential antibacterial agents. Dig J Nanomater Bios 4(2):361–367

    Google Scholar 

  • Stewart JJP (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model 13:1173–1213

    Article  PubMed  CAS  Google Scholar 

  • Xia Y, Yang Z, Hour M, Kuo S, Xia P, Bastow KF, Nakanishi Y, Nampoothiri P, Hackl T, Hamel E, Lee K (2001) Antitumor agents. Part 204: synthesis and biological evaluation of substituted 2-aryl quinazolinones. Bioorg Med Chem Lett 11:1193–1196

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

One of the authors (D. N. Rana) is thankful to UGC-BSR for Research fellowship.

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Correspondence to Pathik S. Brahmkshatriya or Nisha K. Shah.

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Buha, V.M., Rana, D.N., Chhabria, M.T. et al. Synthesis, biological evaluation and QSAR study of a series of substituted quinazolines as antimicrobial agents. Med Chem Res 22, 4096–4109 (2013). https://doi.org/10.1007/s00044-012-0408-0

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  • DOI: https://doi.org/10.1007/s00044-012-0408-0

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