Biopolym. Cell. 2019; 35(5):349-355.
Bioorganic Chemistry
Investigation of Antimicrobial Activity of 1,3-benzoxazine Derivatives
1Zahorulko S. P., 1Varenichenko S. A., 2Farat O. K., 3Markova I. V., 1Markov V. I.
  1. Ukrainian State University of Chemical Technology
    8 Gagarina Ave., Dnipro, Ukraine, 49005
  2. M. V. Lomonosov Moscow State University
    Leninskie Gory, 1/12, Moscow, Russian Federation, 119991
  3. Dnipro National University of Railway Transport named after V. Lazaryana
    2, Lazaryan Str., Dnipro, Ukraine, 49010


Aim. To investigate potential antimicrobial activity of 1,3-benzoxazines derivatives. Methods. Synthesis, antimicrobial screening, antimicrobial and antifungal activity testing in vitro. Results. For antimicrobial screening, we chose the compounds that differed from the investigated ones by 30 %. Five compounds were selected and their antimicrobial activity against five bacterium and two fungus strains was studied by the methods of microbial growth inhibition assay. The percentage of growth inhibition of an individual sample is calculated considering a negative control (media only) and a positive control (bacterial / fungal media without inhibitors). The results obtained showed that compounds 2-[5-(4-nitrophenyl)-1H-pyrazol-3-yl]phenol and 6,8-diisopropylspiro[1,3-benzoxazine-2,1’-cyclohexan]-4(3H)-one in concentration of 32 μg/ml have the highest activity against Acinetobacter baumannii - 43 % and 27 %, respectively. The compound, 6,8-diisopropyl-2-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-1,3-benzoxazine-4-one showed the fungicidal activity against the Candida albicans strain. Conclusion. The derivatives of 1,3-benzoxazines exhibit a moderate antimicrobial activity, which allows the recommendation to continue the search for effective antimicrobials among the chemical compounds of this group, in particular, through the targeted synthesis of new compounds with predicted antimicrobial properties.
Keywords: 1,3-benzoxazines, 1H-pyrazol-3-yl-phenol, antimicrobial screening


[1] Saito T, Ogawa S, Takei N, Kutsumura N, Otani T. Palladium-catalyzed highly regio- and stereoselective synthesis of 4-alkylidene-4H-3,1-benzoxazines from N-acyl-o-alkynylanilines. Org Lett. 2011;13(5):1098-101.
[2] Ilić M, Ilaš J, Dunkel P, Mátyus P, Boháč A, Liekens S, Kikelj D. Novel 1,4-benzoxazine and 1,4-benzodioxine inhibitors of angiogenesis. Eur J Med Chem. 2012;58:160-70.
[3] Zhang P, Terefenko EA, Fensome A, Zhang Z, Zhu Y, Cohen J, Winneker R, Wrobel J, Yardley J. Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines. Bioorg Med Chem Lett. 2002;12(5):787-90.
[4] Zhang Z, Olland AM, Zhu Y, Cohen J, Berrodin T, Chippari S, Appavu C, Li S, Wilhem J, Chopra R, Fensome A, Zhang P, Wrobel J, Unwalla RJ, Lyttle CR, Winneker RC. Molecular and pharmacological properties of a potent and selective novel nonsteroidal progesterone receptor agonist tanaproget. J Biol Chem. 2005;280(31):28468-75.
[5] Charmantray F, Demeunynck M, Carrez D, Croisy A, Lansiaux A, Bailly C, Colson P. 4-Hydroxymethyl-3-aminoacridine derivatives as a new family of anticancer agents. J Med Chem. 2003;46(6):967-77.
[6] Gala F, Dauria MV, De Marino S, Sepe V, Zollo F, Smith CD, Keller SN, Zampella A. Jaspamide M-P: new tryptophan modified jaspamide derivatives from the sponge Jaspis splendans. Tetrahedron. 2009; 65(1): 51-6.
[7] Wang CF, Su YC, Kuo SW, Huang CF, Sheen YC, Chang FC. Low-surface-free-energy materials based on polybenzoxazines. Angew Chem Int Ed Engl. 2006;45(14):2248-51.
[8] Lin CH, Cai SX, Leu TS, Hwang TY, Lee HH. Synthesis and Properties of Flame-Retardant Benzoxazines by Three Approaches. J Polym Sci A. 2006; 44(11): 3454-68.
[9] Ishida H, Ohba S. Synthesis and characterization of maleimide and norbornene functionalized benzoxazines. Polymer. 2005; 46(15): 5588-95.
[10] Burke WJ. 3,4-Dihydro-1,3,2H-Benzoxazines. Reaction of p-substituted phenols with N,N-dimethylol-amines. J Am Chem Soc. 1999; 71(2): 609-12.
[11] Farat OK, Markov VI, Varenichenko SA, Dotsenko VV, Mazepa AV. The Vilsmeier-Haack formylation of 2,3-dihydro-4H-1,3-benzoxazin-4-ones and isomeric 1,2-dihydro-4H-3,1-benzoxazin-4-ones: an effective ap-proach to functionalized 2H-/4H-chromenes and tetrahydroacridines. Tetrahedron. 2015; 71(34): 5554–61.
[12] Zahorulko SP, Varenichenko SA, Farat OK, Mazepa AV, Okovytyy SI, Markov VI. Reactions of 2H(4H)-chromenes with dinucleophiles: one-step synthesis of 2-(1H-(bi)pyrazol-3-yl)- and 2-(1,4(5)-(benzo)diazepin-4-yl)phenols. Chem Heterocycl Comp. 2018; 54(9):859–67.
[13] Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A, Light Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington JP. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res. 2012;40(Database issue):D1100-7.
[14] Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008;36(Database issue):D901-6.