Table 3.

Benzomorpholinone series hit to lead optimisation

Compd	R	IC50 [μm][a]		EC50 [μm][a]		Selectivity	LE[b]
		TbNMT	hNMT	T. brucei	MRC5	ratio	TbNMT
33	H	2.9	>100	ND	ND	–	0.43
34	2-CH3	>100	>100	ND	ND	–	–
35	6-Chloro	>100	>100	ND	ND	–	–
36	7-Chloro	7.1	>100	ND	ND	–	0.37
37	7-Bromo	6.4	>100	ND	ND	–	0.37
38	8-Bromo	11	>100	ND	ND	–	0.37
39		0.008	0.7	0.41	>50	2	0.40
40		<0.002	1.0	0.08	24	13	>0.38
41		<0.002	0.9	0.19	19	5	>0.40
42		0.009	24	0.35	>50	69	0.38
43		<0.002	0.9	0.15	22	6	>0.40
44		<0.002	0.04	0.007	10	6	>0.40

[a] Values shown are the mean of two or more determinations; ND=not determined. [b] Ligand efficiency (LE), determined for compounds with T. brucei NMT potency <50 μm, was calculated as 0.6 ln(IC₅₀)/(heavy atom count) for TbNMT.[11] [c] Selectivity ratio: hNMT (EC₅₀)/T. brucei cell (EC₅₀).