TABLE 2.

DMDP derivatives with modifications at the 5 position (R1) and substitutions on the phenyl group (R2 through R6)  

Derivative no.a	SRI no.c	Substitution at DMDP position						IC50 (nM) for:		Selectivity ratiob
		R1	R2	R3	R4	R5	R6	Human DHFR	MAC DHFR
1	8686	CH3	OCH2CH3	H	H	OCH2CH3	H	2,300	0.84	2,738
2	8117	CH3	OCH3	H	H	OCH3	H	1,000	1.1	909
3	8687c	CH3	OCH2CH3	H	H	OCH2CH3	H	1,000	1.4	714
4	8202	CH3	CH3	H	H	OCH3	H	150	0.40	375
5	9734	CH3	CH3	H	Br	H	CH3	1,900	5.3	358
6	8922	CH2CH3	OCH3	H	H	OCH3	H	1,000	2.8	357
7	8229	CH3	OCH3	H	H	CH3	H	300	0.86	349
8	9786	CH3	OCHF2	H	H	H	H	277	0.87	318
9	9674	CH3	F	H	H	CH3	H	250	1.1	227
10	9717	CH3	Cl	H	CH3	H	CH3	850	3.8	224
11	9643	CH3	Cl	H	H	H	H	120	0.91	132
12	8911	CH2CH3	OCH3	H	H	CH3	H	370	3.1	119
13	9672	CH3	F	H	H	F	H	69	0.90	77
14	9826	CH3	OCH3	H	C6H5	H	H	68	0.91	75
15	9018	CH3	CH3	H	H	CH3	H	57	0.92	62
16	9647	CH3	Cl	H	H	CH3	H	44	0.95	46
17	9782	CH3	Cl	H	F	CH3	H	33	0.78	42.3
18	9645	CH3	H	H	Cl	H	H	27	0.84	32.1
19	8574c	CH3	OCH3	H	H	CF3	H	36	1.2	30
20	8709	CH3	H	OCH3	H	OCH3	H	15	0.64	23.4
21	9675	CH3	CH3	H	H	F	H	19	0.85	22
22	9644	CH3	H	Cl	H	H	H	17	0.82	20.7
23	9787	CH3	H	H	OCHF2	H	H	20	1.1	18
24	9981	CH3	H	OCH3	OCH2CH3	H	H	18	1.1	16.5
25	9980	CH3	H	OCH3	O(CH2)2CH3	H	H	15	0.93	16.1
26	7746	H	H	OCH3	OCH3	OCH3	H	3,900	240	16
27	9827	CH3	H	F	OCH3	H	H	14	0.91	15
28	9596	CH3	CH3	H	Cl	H	H	2.8	0.19	14.7
29	8758	CH2OCH3	OCH3	H	H	OCH3	H	31,000	2,400	12.9
30	8710c	CH3	H	OCH3	H	OCH3	H	8.7	0.73	11.9
31	9733	CH3	OCH3	H	Cl	CH3	H	10	0.94	10.6
32	8577	H	H	H	Cl	H	H	670	73	9.2
33	9646	CH3	Cl	H	H	Cl	H	8.0	0.89	9.0
34	9595	CH3	CH3	H	H	Cl	H	6.1	0.79	7.7
35	9600	CH3	H	Cl	CH3	H	H	6.7	0.90	7.44
36	8692	CH3	H	OCH3	OCH3	H	H	5.1	0.70	7.29
37	9614	CH3	H	CH3	Br	H	H	6.1	0.87	7.01
38	9613	CH3	CH3	H	Br	H	H	5.9	0.85	6.94
39	9676	CH3	Br	H	H	Br	H	4.6	0.70	6.6
40	9599	CH3	CH3	Cl	H	H	H	5.2	0.82	6.34
41	9612	CH3	H	Br	CH3	H	H	3.7	0.60	6.17
42	8227	CH3	H	OCH3	H	CF3	H	5.5	0.93	5.91
43	7714	CH3	H	OCH3	OCH3	OCH3	H	4.7	0.82	5.7
44	9632	CH3	H	Cl	Cl	H	H	5.0	0.92	5.43
45	8766	CH2OCH3	H	OCH3	OCH3	H	H	6,100	1,200	5.1
46	9684	CH3	F	H	H	CF3	H	4.1	0.86	4.8
47	8228	CH3	OCH3	H	H	CF3	H	2.7	0.66	4.1
48	8923	CH2CH3	OCH3	H	H	CF3	H	3.6	0.88	4.1
49	9683	CH3	Br	H	H	CF3	H	3.2	0.82	3.9
50	8765	CH2OCH3	H	OCH3	OCH3	OCH3	H	1,300	550	2.4
51	8759	CH2OCH3	H	H	Cl	H	H	2,600	1,500	1.76

^aDerivatives are listed in descending order by selectivity ratio (see last column). 

^bSelectivity ratio equals IC₅₀ human DHFR/IC₅₀ MAC DHFR. 

^c H group on N¹⁰ link is replaced with CH₃. SRI, Southern Research Institute.