Calcd (C14H24N8O4) C 45.64, H 6.57, N 30.42; Found out: C 45.29, H 6.73, N 29.58. 2,6-Bis(diethanolamino)-4,8-dimethylamino-pyrimido[5,4-397 (M + H)+, 419 (M + Na)+, 435 (M + K)+; 1H NMR (DMSO-7.154 (q, 2H, 2 N= 4.5 Hz), 4.675 (br s, 4H, 4 OH, disappeared after D2O), 3.676 (t, 8H, 2 N(C= 4.5 Hz); Anal. is the prototype, pyrimidopyrimidine analogs such as the antithrombotic and vasodilating agent dipyridamole, and flazine calcium channel blockers displayed by lidoflazine. Open in a separate window Number 1 Representatives of the three main ENT1 inhibitory chemical classes NBMPR is definitely a more potent ENT1 inhibitor (e.g. purine biosynthetic pathways.33 Nucleoside transporters of parasites have limited homologies with the human being ENT1, and have been demonstrated to be inhibited by dipyridamole but not NBMPR or lidoflazine. 34 Some parasites 4E2RCat like can even transport NBMPR.35 A study of the antimalarial activity of dipyridamole showed that it was effective against all the erythrocytic stages such as rings, trophozoites and schizonts; it experienced an IC50 of 30 nM by itself, and lowered the IC50 of chloroquine from 97.0 nM to 13.7 nM at a concentration of 0.1 nM.36 In light of these positive attributes of dipyridamole, we selected it as a candidate for further structure-activity relationship (SAR) exploration for ENT1 transporter inhibitory activity. Many dipyridamole analogs have been reported, and evaluated for their effects as antiplatelet and cardioprotective providers.37-41 Some dipyridamole analogs have also been synthesized and evaluated for his or her inhibitory activities against cyclin dependent kinases (CDKs), with bad results.42 A more recent publication disclosed the synthesis and biological evaluation of a series of dipyprdamole analogs for his or her ENT1 inhibitory activities, and some of them showed only slightly higher activities than dipyridamole.43 With this paper, a series of dipyridamole analogues were 4E2RCat synthesized for a more systematic and comprehensive evaluation of ENT1 SAR. Some of the compounds showed comparative activity to NBMPR, which is a much more potent ENT1 inhibitor than dipyridamole. Chemistry For the synthesis of these dipyridamole analogs, commercially available starting materials, 2,4,6,8-tetrachloropyrimido[5,4-417 (M + H)+, 439 (M + Na)+; 1H NMR (DMSO-6.016 (t, 2H, 2 NH, disappeared after D2O, = 5.5 Hz), 4.606 (t, 2H, 2 OH, disappeared after D2O, = 5.5 Hz), 4.057 (br s, 8H, 2 N(C= 6 Hz, = 5.5 Hz), 3.269 (q, 4H, 2 NHC= 5.5 Hz, = 6 Hz), 1.641 (br d, 4H, 2 N(CH2CH2)2C= 4.5 Hz), 1.592 (br d, 8H, 2 N(CH2C= 4.5 Hz); Anal. (C20H32N8O2) C, H, N. 2,6-Bis(diethanolamino)-4,8-dipyrrolidinyl-pyrimido[5,4-477 (M + H)+; 1H NMR (DMSO-4.688 (m, 4H, 4 OH, disappeared after D2O exchange), 4.119 (br s, 8H, 2 N(C389 (M + H)+, 411 (M + 4E2RCat Na)+; 1H NMR (DMSO-5.774 (t, 2H, 2 NH, disappeared after D2O), 4.591 (t, 2H, 2 OH, disappeared after D2O exchange), 4.006 (br s, 8H, 2 N(C= 6 Hz), 3.292 (q, 4H, 2 NHC= 6 Hz), 1.863 (br s, 8H, 2 N(CH2C4.689 (t, 4H, 4 OH, disappeared after D2O), 4.121 (br s, 8H, 2 N(C421 (M + H)+, 443 (M + Na)+; 1H NMR (DMSO-6.186 (t, 2H, 2 NH, disappeared after D2O), 4.619 (t, 2H, 2 OH, disappeared after D2O), 4.128 (br s, 8H, 2 N(C535 (M + H)+, 557 (M + Na)+; 1H NMR (DMSO-4.719 (t, 4H, 4 OH, disappeared after Rabbit Polyclonal to CDK5R1 D2O), 4.122 (br s, 8H, 2 N(C707 (M + H)+, 729 (M + Na)+; 1H NMR (DMSO-4.749 (br t, 4H, 4 OH, disappeared after D2O), 4.121 (br s, 8H, 2 N(C641 (M + H)+, 663 4E2RCat (M + Na)+; 1H NMR (DMSO-7.388 (d, 3H, Ar-H-3, Ar-H-4, Ar-H-5), 7.335 (m, 2H, Ar-H-2, Ar-H-6), 5.121 (s, 2H, 4E2RCat PhC503 (M + H)+, 525 (M + Na)+; 1H NMR (DMSO-4.782 (t, 4H, 4 OH, disappeared after D2O), 3.717 (br s, 8H, 2 N(C491 (M + H)+, 513 (M + Na)+; 1H NMR (DMSO-8.470 (m, 4H, 2 Ar-H-2, 2 Ar-H-6), 7.557 (m, 6H, 2 Ar-H-3, 2 Ar-H-4, 2 Ar-H-5), 4.805 (t, 4H, 4 OH, disappeared after D2O, = 5Hz), 3.793 (br s, 8H, 2 N(C= 5Hz); Anal. (C26H30N6O4).