Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates

Abstract

Two classical antifolates, a 2,4-diamino-5-substituted furo [2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted pyrrolo [2,3-d]pyrimidine, were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The syntheses were accomplished by condensation of 2,6-diamino-3(H)-4-oxo-pyrimidine with α-chloro-ketone 21 to afford two key intermediates 23 and 24, followed by hydrolysis, coupling with L-glutamate diethyl ester and saponification of the diethyl ester to afford the classical antifolates 13 and 14. Compounds 13 and 14 with a single carbon atom bridge are both substrates for folylpoly-γ-glutamate synthetase (FPGS), the enzyme responsible for forming critical poly-γ-glutamate antifolate metabolites with increased potency and/or increased cell retention. Compound 14 is a highly efficient FPGS substrate demonstrating that 2,4-diamino-5-substituted furo [2,3-d]pyrimidines are important lead structures for the design of antifolates with FPGS substrate activity. It retains inhibitory potency for DHFR and TS compared to the two atom bridged analog 5. Compound 13 is a poor inhibitor of purified DHFR and TS, and both 13 and 14 are poor inhibitors of the growth of CCRF-CEM human leukemia cells in culture, indicating that single carbon bridged compounds in these series though conducive to FPGS substrate activity were not potent inhibitors.

Antimony(III) complexes with 2-amino-4,6-dimethoxypyrimidines: Synthesis, characterization and biological evaluation

“…As shown in Fig. 4, two reduction peaks for (2) were obtained at about − 0.6 V and − 0.8 V. Increasing of peak height at −0.6 V with addition of Sb(III) solution to the medium indicated that this peak can be assigned to reduction of Sb(III) to Sb(0). Chronoamperometric measurements also show that transferred electron number in this electrochemical reduction was 3.…”

“…Chronoamperometric measurements also show that transferred electron number in this electrochemical reduction was 3. The other peak showing no change is adsorption peak of the (2).…”

“…Synthesis of bis(2-amino-5-thiol-4,6-dimethoxypyrimidine) trichloroantimony(III) (2) 0.52 g 2-amino-4,6-dimethoxy-5-thiocyanatopyrimidine (1) was dissolved in acetonitrile and 0.28 g antimony(III) chloride was added to the solution in the mole ratio of 2:1. The mixture was refluxed for 4 days at 82°C.…”

“…On the basis of previous virtual screening, we planned to obtain new antimony(III) compounds containing sulfide bridge, pyrimidine, and/or tetrazole groups to develop novel multitargetdirected drugs. As part of our ongoing works, in this study, three antimony(III) compounds, dimeric [Sb(5,5′-disulfanediylbis(2-amino-4,6-dimetoxypyrimidine))Cl 3 ] 2 , and monomeric Sb(2-amino-5-thiol-4,6-dimethoxypyrimidine) 2 Cl 3 (4) and (2-amino-5-(1H-tetrazol-5-ylthio)-4,6-dimethoxypyrimidine) 2 Cl 3 (6) were synthesized and identified by using IR, NMR, LCMR, conductivity and calculation with a DFT/B3LYP/LANL2DZ method. In addition, 5,5′-disulfanediylbis(2-amino-4,6-dimetoxypyrimidine) was obtained by reduction of 2-amino-4,6-dimethoxy-5-thiocyanatopyrimidine for the first time and its structure was identified by X-ray crystallographic analysis.…”

“…Pyrimidines present a wide range of biological activities [1], as antifolate [2], antimicrobial [3,4], antifungal [5], anti-rubella [6], anti-HIV [7], antiviral [8], anti-inflammatory [9], antitumor [10,11], antimalarial [12,13] and antileishmanial [14][15][16][17][18][19][20] agents. On the other hands, tetrazoles exhibit appreciable biological activity [21], including glutathione reductase inhibitory activity [22] and antileishmanial activity against Leishmania braziliensis promastigotes [23].…”