Dihydrofolate reductase inhibitors among pteridine and fu-ro[3,2-g]pteridine derivatives

Abstract

To the purposeful search for the DHFR-inhibitors among substituted pteridine-2,4,7triones 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 estab- 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. The obtained compounds may be of interest for further studies aimed at the search for anti-inflammatory, anti-viral, hypoglycemic, hypotensive, anti-ische mic agents due to the expected low-toxicity associated with the slight DHFR-inhibiting activity.

Evaluation of the toxicity and hepatoprotective properties of new s-substituted pteridins

“…Current Issues in Pharmacy and Medical Sciences [7][8][9][10][11][12][13][14]. Moreover, the folates themselves, as noted above, are essential nutrients and are involved in various metabolic processes, including the formation of methionine, which in turn is used for the synthesis of S-adenosylmethionine, as a universal donor of the methyl group [6].…”

Тhio‐containing pteridines: Synthesis, modification, and biological activity

“…Thus, thio-containing pteridines are promising biologically active compounds and can be used for the treatment of widespread and severe diseases including cancer, inflammatory processes, and neurodegenerative pathologies. The present paper is a sequel to our previous investigations aimed at the search for biologically active compounds among substituted pteridines [9][10][11][12] and is devoted to the search for DHFR inhibitors among a series of thio-contained pteridines that are structurally similar to the known medicines with this mechanism of action (Figure 1). [13] Evaluation of radical-scavenging activity of obtained compounds was the additional aim of the present study.…”