TABLE 2.

Optimization of benzimidazole-based FabI inhibitors and prediction of in vivo hepatic clearance in BALB/c mouse

Compd	R1	R2	R3	cLogP	FabI Inhibitiona	Microsomal Stability		Serum/Microsomal Free Fraction		Hepatic Clearance	Hepatic Extraction Ratio
					IC50 (μM)	t1/2 (min)	Clint, app (μl/min/mg)	fu, s	fu, m	Clh (ml/min/kg)
23	CH2	CH3	3′-H, 4′-Cl, 5′-Cl, 6′-H, 7′-H	5.77	0.043	20.0	69	0.001	0.017	7	0.1
24	CH2	H	3′-H, 4′-H, 5′-OCH3, 6′-H, 7′-H	4.28	0.84	2.9	474	0.022	0.299	38	0.4
25	CH2	H	3′-H, 4′, 5′-OCH2O, 6′-H, 7′-H	4.22	2.2	4.6	304	0.021	0.263	30	0.3
26	CH2	H	3′-H, 4′-CH3, 5′-OCH3, 6′-H, 7′-H	4.74	0.005	2.1	672	0.006	0.086	45	0.5
27	O	CH3	3′-H, 4′-Cl, 5′-Cl, 6′-H, 7′-H	4.28	0.89	14.8	94	0.034	0.393	13	0.1
28	O	H	3′-H, 4′-H, 5′-OCH3, 6′-H, 7′-H	2.78	5.3	5.9	235	0.183	0.816	47	0.5
29	O	H	3′-H, 4′, 5′-OCH2O, 6′-H, 7′-H	2.73	11.8	20.4	68	0.201	0.791	24	0.3
30	O	H	3′-H, 4′-CH3, 5′-OCH3, 6′-H, 7′-H	3.24	0.12	1.4	980	0.158	0.812	72	0.8
31	O	H	3′-H, 4′-OCH3, 5′-OCH3, 6′-H, 7′-H	2.60	22.4	18.6	75	0.293	0.855	31	0.3

^aFabI IC₅₀ values determined per published procedures (Hevener et al. 2012) with reduced FabI concentration of 10 nM.