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. Author manuscript; available in PMC: 2011 May 13.
Published in final edited form as: J Med Chem. 2010 May 13;53(9):3685–3695. doi: 10.1021/jm100057h

Table 7.

Efficacy and ADMET parameters for the development of a treatment for uncomplicated malaria caused by Plasmodium falciparum in adults and children.

Parameter Minimum Essential Ideal Compound 18 Compound 4
In silico profiling, Lipinski “Rule of 5” violations <2 0 0 0
In vitro potency (IC50, nM, W2 strain) <2000 <100 5.6 17.3
Bacterial mutagenicity, AMES test <3-fold increase in mutagenicity no increase in mutagenicity no increase in mutagenicity no increase in mutagenicity
Metabolic stability, t½ human microsomes >0.5 h >4 h 1.5 h (1 μM), 4.6 h (10 μM) 0.80 h (1 μM), 1.8 h (10 μM)
Permeability, PAMPA pH 7.4/7.4sink >100 × 10-6 cm/s >1000 × 10-6 cm/s 2400 × 10-6 cm/s 1109 × 10-6 cm/s
In vitro P450 inhibition (inhibition of CYP isoforms at 1μM concentration) Only CYP2D6 none none significant none significant
Cytotoxicity, primary rat hepatocytes, ratio TC50 to IC50 W2 >20 >100 1340 2313
t1/2 (h, rodent) >2 >8 6.8 15.9
Cmax (nM, rodent) >80 >200 240 436
AUC (nmoles*h/L, rodent) >300 >1000 2026 6792