Table 1 Structure-activity relationships of monomeric dCym derivatives and Homo-BacPROTACs View full size image

From: Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria

Entry

Compound

 

R1

R2

R3

ClpC1-NTD KD[a] [nM] Mean ± SD

MIC Mtb H37Rv[b] [µM] Mean ± SD

Influence of N-methylation on permeability[c]

1

dCymC

Monomer

H

1.1 ± 0.4

0.4 ± 0.1

1.6

23

Me

12.1 ± 0.3

n.d.

2

10

Monomer

H

Me

4.0 ± 0.7

3.1 ± 0.0

>11.8

20

Me

13.9 ± 0.3

50.0 ± 0.0

3

24

Monomer

H

Me

A

4.6 ± 0.2

n.d.

>1.5

25

Me

26.1 ± 0.1

6.3

4

12 (UdSBI-4377)

Dimer

H

Me

B

0.28 ± 0.08

0.1 ± 0.0

n.d.

22

Me

0.9 ± 0.3

3.1 ± 0.0

5

5

Monomer

H

iPr

3.5 ± 0.1

1.6

9.3

26

Me

15 ± 3

6.3

6

8 (UdSBI-0545)

Dimer

H

E

iPr

0.4 ± 0.1

0.4 ± 0.4

n.d.

27

Me

0.4 ± 0.2

<0.1

7

6

Dimer

H

C

iPr

0.9 ± 0.4

0.4 ± 0.3

–

8

11

Dimer

H

Me

D

0.4 ± 0.2

0.1 ± 0.0

–

9

15

Dimer

H

iPr

1.2 ± 0.8

0.2 ± 0.1

n.d.

28

Me

1.8 ± 0.1

n.d.

  1. KD and MIC values are reported as mean ± SD. The number of measurements performed for each compound are indicated by footnotes in Supplementary Tables 1 and Table 2.
  2. aDissociation constant KD towards ClpC1-NTD measured by surface plasmon resonance.
  3. bMinimum inhibitory concentrations against M. tuberculosis H37Rv strain.
  4. cDetermined by comparison of efflux ratios across Caco-2 monolayers for matched pairs: Reff (N-H)/Reff (N-Me). n.d.: not determined. Bold numbers refer to compounds described in the text.
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