Table 5.

Variation of R² substituent for N-methylated aminopyrazoles yields C. neoformans- and C. albicans-selective Hsp90 inhibitors with diverging isoform selectivities. Fold selectivities > 5 are highlighted in red.

Entry	Compound	R2	X	C. neoformans EC50a (μM)	C. neoformans fold- selectivityb	C. albicans EC50c (μM)	C. albicans fold- selectivityb
1	100	iPr	A	0.087	0.9	0.048	0.6
2	101		B	0.062	1.6	0.156	0.2
3	102		C	0.040	3.0	0.094	0.5
4	103	Cy	A	0.156	0.7	0.033	1.4
5	104		B	0.110	6.5	0.670	0.4
6	105		C	0.037	3.7	0.096	0.6
7	106		A	0.065	14.1	0.599	0.7
8	107		B	0.139	12.9	0.795	0.8
9	108		C	0.084	12.4	0.398	0.9
10	109		A	0.267	16.3	0.573	3.0
11	110		B	0.421	15.1	1.030	2.4
12	111		C	0.176	14.6	0.396	2.5
13	112		A	0.281	33.3	1.642	2.0
14	113		B	0.852	27.6	5.000	1.7
15	114		C	0.244	26.5	1.881	1.3
16	115		A	4.601	3.2	2.236	2.1
17	116		B	1.523	5.5	0.594	4.4
18	117		C	0.434	9.8	0.294	4.6
19	118		A	1.318	6.3	1.067	2.6
20	119		B	1.781	9.5	1.779	4.0
21	120		C	0.424	14.9	0.636	3.4
22	121		A	0.630	4.4	0.186	5.8
23	122		B	1.289	6.9	1.139	3.1
24	123		C	0.489	6.8	0.376	3.4
25	124		A	9.530	1.0	1.084	3.1
26	125		B	5.815	0.8	0.319	4.8
27	126		C	1.385	1.1	0.103	4.9
28	127		A	>10	-	1.197	2.1
29	128		B	8.337	0.4	0.237	4.5
30	129		C	2.262	0.5	0.071	5.0
31	130		A	5.402	1.0	0.134	15.3
32	131		B	1.262	1.0	0.050	18.2
33	132		C	0.514	1.3	0.016	15.9

EC₅₀ and selectivity values were determined as described for Table 1.