Biopolym. Cell. 2021; 37(2):143-152.
Bioorganic Chemistry
Dihydrofolate reductase inhibitors among pteridine and furo[3,2-g]pteridine derivatives
1Nosulenko I. S., 1Kazunin M. S., 1Kinichenko A. O., 1Antypenko O. M., 2Zhurakhivska L. R., 1Voskoboinik O. Yu., 1Kovalenko S. I.
  1. Zaporizhia State Medical University
    26, Mayakovsky avenue, Zaporizhzhia, Ukraine, 69035
  2. Lviv Polytechnic National University
    12, S. Bandery Str., Lviv, Ukraine, 79013


Aim. To the purposeful search for the DHFR-inhibitors among substituted pteridine-2,4,7-triones and 7-aryl-(hetaryl-)furo[3,2-g]pteridine-2,4(1H,3H)-diones for further biological research. Methods. In vitro methods, molecular docking, SAR-analysis, statistical methods. Results. The DHFR-inhibitory activity of substituted 1-methylpteridine-2,4,7-triones (2, 3, 4) and 7-aryl-(hetaryl-)furo[3,2-g]pteridine-2,4(1H,3H)-diones (5, 6) was studied. It was established that 6-(2-hydroxy-2-aryl-(hetaryl-)ethyl)-1-methylpteridine-2,4,7(1H,3H,8H)-triones (3) and butyl 2-(7-aryl- (hetaryl-)-1-methyl-2,4-dioxo-1,4-dihydrofuro[3,2-g]pteridine-3(2H)-yl)acetates (6) inhibited DHFR by 14.59–52.11 %, and were less active comparing to methotrexate. It was found that the introduction of aryl moiety with electron-accepting group, naphthyl substituent or electron-accepting heterocycle (furan, thiophene and benzofuran) caused an increase in the DHFR-inhibitory activity. Additionally, it was shown, that annulation of the furan cycle to the pteridine system was reasonable in the scope of new DHFR-inhibitors synthesis. Thereby it may be concluded that the calculated values of affinity are not reliable predictors for the DHFR-inhibiting activity of studied compound. However, the molecular docking study may be used for evaluation of the interactions between the studied inhibitor and active center of DHFR. Conclusions. The conducted primary in vitro screening revealed low or moderate DHFR-inhibiting activity of the synthesized compounds. The visualization of molecular docking showed that despite the structural similarity to methotrexate, the obtained compounds form different ligand-enzyme interactions. The calculated values of affinity cannot be used as predictors of DHFR-inhibiting activity because of the absence of correlation between the abovementioned indicators.
Keywords: DHFR-inhibiting activity, pteridine, furo[3,2-g]pteridine, molecular docking, QSAR-analysis


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