Table 1. Propargyl-linked DHFR inhibitors^a inhibit the S. aureus and S. pyogenes DHFR enzymes.

Number	Ar	R6	RP	R2′	R3′	IC50 (nM)			Selectivity
						Sab	Spb	Humanb	(h/Sa)c	(h/Sp)c
1	3,5-dimethyl phenyl	Me	Me	H	OMe	42±2	190±15	750±6	18	4
2	4-methyl phenyl	Me	Me	H	OMe	410±36	350±44	1400±15	3	4
7	phenyl	Et	H	OMe	H	2.4±0.2	5.9±0.2	300±10	125	51
8	phenyl	Et	H	H	H	28±1.7	26±1.7	290±36	10	11
9	phenyl	Et	H	H	OMe	59±2.3	52±1.7	140±1.0	2.4	3
10	phenyl	Me	Me	OMe	H	75±4	23±1.5	97±10	1.3	4
11	phenyl	Et	Me	OMe	H	67±5.5	26±2.5	100±10	1.5	4
24	4-pyridyl	Me	Me	H	OMe	26±2	160±9	1500±8	58	9.4
25	4-pyridyl	Et	Me	H	OMe	19±1	180±19	1300±11	68	7.2
26	4-pyridyl	Et	H	OMe	H	21±1.0	19±1.3	330±12	16	17
27	4-pyridyl	Et	H	H	OMe	12±2.4	28±4.0	61±5.7	5	2
28	4-pyridyl	Et	H	H	H	20±0.5	30±1.7	520±23	26	17
31	morphilino	Me	Me	H	OMe	29±2	26±4	400±40	14	15
36	3-pyridyl	Et	H	H	H	33±0.5	47±4.6	290±15	9	6
37	4-pyrimidinyl	Et	H	H	H	35±1.1	23±1.2	160±13	5	7
TMP						23	13000	198000	8600	15

^aThe generalized scaffold for the propargyl-linked inhibitors is shown in Figure 1a.

^bIC₅₀ values against the DHFR enzymes are reported in nM and represent the average of at least three measurements.

^cSelectivity is calculated as IC₅₀ (human)/IC₅₀ (pathogen).