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. Author manuscript; available in PMC: 2019 Apr 13.
Published in final edited form as: ACS Infect Dis. 2017 Nov 7;4(4):549–559. doi: 10.1021/acsinfecdis.7b00159

Table 2.

Growth Inhibition (P. falciparum, E. coli) and Pf IspD Inhibition of D-Ring Variants of 1a

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compounda X P. falciparum growth inhibition IC50 (nM)c % recovery (200 μM IPP)e PfIspD IC50 (nM)f % E. coli growth inhibition (18 h)h
1b H >10 000d ND >5000g NI @ 250 μM
1c 2′-Cl 3280 ± 990d 60 ± 5 @ 10 μM ~1000 NI @ 250 μM
1d 4′-Cl 1170 ± 60d 50 ± 7 @ 10 μM 510 ± 90 NI @ 250 μM
1e 2′-Cl,4′-Me 410 ± 40d 100 @ 2.5 μM 82 ± 10 NI @ 500 μMc
1f 2′-Me,4′-Cl 700 ± 90d 100 @ 2.5 μM 260 ± 50 NI @ 500 μMc
1g 2′,4′-F2 780 ± 175d 100 @ 5 μM 230 ± 10 NI @ 500 μMc
1h 2′-F,4′-Cl 860 ± 80 100 @ 5 μM 140 ± 30 NI @ 250 μM
1i 2′-Cl,4′-F 433 ± 55 100 @ 10 μM 100 ± 10 NI @ 250 μM
1j 2′-Cl,4′-Br 320 ± 60 100 @ 5 μM 34 ± 11 NI @ 250 μM
1k 2′-Br,4′-Cl 360 ± 40 100 @ 5 μM 31 ± 4 NI @ 125 μM
1l 2′,4′-Br2 590 ± 20 100 @ 10 μM 84 ± 14 NI @ 125 μM
1m 2′-I,4′-F 970 ± 180 100 @ 10 μM 140 ± 70 NI @ 250 μM
1n 2′-F,4′-I 3343 ± 496 100 @ 10 μM 130 ± 20 NI @ 125 μM
1o 2′-Br,4′-I 1500 ± 200 80 ± 5 @ 10 μM ND ND
1p 2′-Cl,4′-OMe >5000 ND ND ND
1q 2′-OMe,4′-Cl 2500 ± 600 ND ND ND
1rb 2′-Cl,4′-OH >5000 ND ND ND
1s 2′-Cl,4′-CO2H NI @ 10 000 ND ND ND
1t 2′,4′-(CF3)2 >10 000d ND >5000g NI @ 250 μM
1u 2′,4′-Me2 70% inh. @ 10 000d ND ~1000 NI @ 250 μM
1v 2′,4′-(OMe)2 >20 000d ND >5000g NI @ 250 μM
1w 3′,4′-Cl2 >10 000 ND NI @ 500 nM NI @ 250 μM
1x 3′,4′-(OMe)2 >20 000d ND ND ND
1y 2′,6′-F2,4′-Cl 1800 ± 150 80 ± 8 @ 10 μM ND ND
1z 2′,3′,4′-F3 ~20 000 ND ND ND
1aa 2′-Br,4′-F,5′-OMe >10 000 ND ND ND
1ab NA >10 000 ND ND ND
1ac NA >5000 ND ND ND
1ad NA >10 000 ND ND ND
1ae NA >10 000 ND ND ND
1af NA >5000 ND ND ND
a

All compounds are trans-configured and derived from (S)-Trp-OMe; all are (1R,3S) except for 1ac, which is (1S,3S) due to a Cahn-Ingold-Prelog priority switch.

b

This compound was tested as an approximate 1:1 mixture of the (1R,3S) and (1S,3S)-stereoisomers.

c

MRA-150, chloroquine-resistant (intermediate), pyrimethamine-resistant, mefloquine-resistant.

d

Data reported previously.13

e

Drug at indicated concentration.

f

Recombinant P. falciparum IspD IC50 values measured at 60 nM Pf IspD.

g

Approximately 10% inhibition at 1000 nM.

h

NA signifies “not applicable”. NI signifies “no inhibition”. ND signifies “not determined”. Values represent averages of at least two independent assays ± SEM.