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. Author manuscript; available in PMC: 2018 Jul 13.
Published in final edited form as: J Med Chem. 2017 Jun 19;60(13):5392–5406. doi: 10.1021/acs.jmedchem.7b00059

Table 1.

Physicochemical properties and biological activities of the 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas 3 and 1-(para-aryloxyphenyl)-3-arylureas 6.

R1 R2 X R3 R4 R5 R6 Surrogate eIF2α @ μM IC50b [μM] cLogP tR [min]
1.25 5
3a H H C CF3 CF3 H H 3.23±0.18 10.16±0.52 0.54±0.1 6.41 19.7
3′a H H C OCF3 CF3 H H 3.37±0.61 10.08±0.51 0.82±0.2 6.48 20.2
Substitution of electron withdrawing groups on the 4-aryloxycyclohexyl moiety bearing a N-(3-trifluromethyl)phenyl ring
3a CONH2 H C CF3 CF3 H H 0.91±0.03 1.49±0.01 2.76±0.4 5.07 16.3
3b H CONH2 C CF3 CF3 H H 0.79±0.03 1.12±0.02 3.36±0.5 4.87 15.6
3c NHCOCH3 H C CF3 CF3 H H 0.84±0.12 3.9±0.02 1.46±0.4 5.17 17.5
3d NO2 H C CF3 CF3 H H 0.96±0.02 3.28±0.12 5.51±1.4 6.01 19.2
3h – H N CF3 CF3 H H 1.02±0.10 6.11±0.11 1.57±0.2 5.66 19.1
3i CN H C CF3 CF3 H H 1.01±0.07 6.3±0.18 1.47±0.3 6.00 18.8
3j H H C CN CF3 H H 0.92±0.06 3.23±0.23 6.06±1.0 4.84 17.4
p- CF3 vs p-CN substituents on the phenylcyclohexyl moiety
3e H H C CF3 CF3 H CF3 8.58±0.13 30.72±0.77 0.45±0.03 7.48 21.7
3f H H C CF3 CN H H 0.96±0.08 7±0.12 0.94±0.1 5.13 17.9
3g H H C CF3 H CN H 3.38±0.21 11.63±0.05 0.49±0.02 5.13 17.8
3k H H C CN H CN H 1.03±0.01 1.38±0.13 9.03±3.1 3.76 15.1
3l H H C CN CN H H 1.01±0.02 1.15±0.08 8.2±1.2 3.76 15.2
N-phenyl ring bearing nitrile groups
3r H H C CF3 CN H CF3 5.65±0.28 13.16±1.36 0.25±0.02 6.20 19.9
3s H H C CF3 CN CN H 5.54±1.34 7.75±1.97 2.01±0.7 4.81 18.3
3t H H C CF3 CN H CN 1.51±0.39 2.36±0.14 3.68±1.1 4.81 18.4
Substitution of electron withdrawing groups on the 4-aryloxycyclohexyl moiety bearing a N-(3-trifluoromethoxy)phenyl ring
3m CONH2 H C CF3 OCF3 H H 0.88±0.09 5.13±0.02 1.53±0.4 3.93 16.6
3n H CONH2 C CF3 OCF3 H H 1.04±0.06 1.57±0.18 3.66±0.9 3.73 16.0
3o NHCOCH3 H C CF3 OCF3 H H 0.85±0.06 4.31±0.13 1.5±0.3 4.97 17.9
3p H H C OCF3 OCF3 H H 2.87±0.16 10.70±0.19 1.45±0.2 6.28 20.3
3q H H C CF3 OCF3 H H 5.2±0.08 13.6±0.70 0.92±0.1 6.21 20.1
para-(4-substituted)phenoxy)phenyl-containing 1,3-diarylureas
6a H H C CF3 CF3 H H 3.31±0.24 8.99±0.1 0.44±0.1 7.40 20.5
6b H H C CF3 OCF3 H H 2.37±0.03 6.73±0.22 0.5±0.2 7.20 20.9
a

Reported previously in Ref. 9.

b

Concentration that inhibits 50% of human CRL-2813 melanoma cell growth.