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. Author manuscript; available in PMC: 2019 Feb 8.
Published in final edited form as: J Med Chem. 2018 Jan 5;61(3):1182–1203. doi: 10.1021/acs.jmedchem.7b01654

Table 1.

SAR of pyrimidine C5 and C6 positions

graphic file with name nihms967105u2.jpg
Compound R1 R2 pKa(N1)a Tb IC50,b μM Hs IC50,c μM Tb427 EC50,d μM
7 H Me 7.3 3.7 (3.3–4.1) 27% at 180 5.6 (4.5–7.1)
8 H H 6.6 13 (11–15) >180 9.9 (7.7–13)
9 H Et 7.1 3.0 (2.7–3.3) 36% at 180 4.7 (4.1–5.4)
10 H iPr 7.0 12 (10–14) >180 4.7 (3.9–5.8)
11 H Ph 6.1 24% at 21 >21 7.2 (6–8.5)
12 H N-morpholino 6.0 >180 >180 13 (10–17)
13 H Cl –2.2 >180 >180 8.9 (7.3–11)
14 H CF3 –3.3 >180 >180 10 (7.5–14)
15 −(CH2)3−         6.8 12 (11–14) >21 19 (15–24)
16 Me Me 7.0 4.8 (4.5–5.2) 25% at 180 17 (14–20)
a

The pKa value of the conjugated acid of the pyrimidine nitrogen N1 estimated using MarvinSketch.

b

Mean IC50 for T. brucei AdoMetDC/prozyme at pH 7.2 determined using the RapidFire–MS-based enzyme activity assay, in triplicate, with 95% confidence interval (CI) shown in parentheses.

c

Mean IC50 for human AdoMetDC at pH 7.2 determined in the RapidFire–MS-based enzyme activity assay, in triplicate, with 95% CI shown in parentheses.

d

Mean EC50 as measured in the ATP–bioluminescence-based bloodstream form T. brucei Lister 427 cell viability assay, in triplicate, with 95% CI shown in parentheses. Percent inhibition at the maximal tested concentration (in μM) is shown when maximum mean inhibition was <50%.