Benzimidazole analogs as WTA biosynthesis inhibitors targeting methicillin resistant Staphylococcus aureus

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx

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Benzimidazole analogs as WTA biosynthesis inhibitors targeting methicillin resistant Staphylococcus aureus Shu-Wei Yang a,⇑, Jianping Pan a, Christine Yang a, Marc Labroli a, Weidong Pan a, John Caldwell a, Sookhee Ha b, Sandra Koseoglu c, Jing C. Xiao c, Todd Mayhood c, Payal R. Sheth c, Charles G. Garlisi c, Jin Wu d, Sang Ho Lee e, Hao Wang e, Christopher M. Tan e, Terry Roemer e, Jing Su a a

Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States Structure Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States In Vitro Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States d Pharmacokinetics PPDM, Merck Research Laboratory, Kenilworth, NJ 07033, United States e Infectious Disease, Merck Research Laboratory, Kenilworth, NJ 07033, United States b c

a r t i c l e

i n f o

Article history: Received 12 July 2016 Revised 11 August 2016 Accepted 12 August 2016 Available online xxxx Keywords: WTA Wall teichoic acid Antibacterial MRSA

a b s t r a c t A series of benzimidazole analogs have been synthesized to improve the profile of the previous lead compounds tarocin B and 1. The syntheses, structure–activity relationships, and selected biochemical data of these analogs are described. The optimization efforts allowed the identification of 21, a fluoro-substituted benzimidazole, exhibiting potent TarO inhibitory activity and typical profile for a wall teichoic acid (WTA) biosynthesis inhibitor. Compound 21 displayed a potent synergistic and bactericidal effect in combination with imipenem against diverse methicillin-resistant Staphylococci. Ó 2016 Elsevier Ltd. All rights reserved.

Multidrug resistant bacteria pose a serious threat to global human health. These organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), are widely clinically resistant to nearly all blactam antibiotics, perhaps our most important class of antibiotics.1 MRSA is also a major cause of bloodstream infection and second leading cause of mortality caused by bacterial pathogens in the United States.2,3 Accordingly, new antibiotics displaying novel mechanisms of actions are urgently needed. A combination agent therapy strategy of combining a b-lactam and b-lactamase inhibitor has been successfully applied to restore b-lactam efficacy against life threatening multidrug resistant Gram-negative bacterial pathogens.4 Therefore a similar approach was sought to restore MRSA and MRSE susceptibility of b-lactams by identifying and chemically optimizing novel adjuvants that are synergistic when paired with existing b-lactams against methicillin-resistant Staphylococci.5–7 Wall teichoic acid (WTA) are broadly conserved Gram-positive bacterial cell wall glycopolymers attached to peptidoglycan and extending out to the cell surface. WTA functionally contributes to ⇑ Corresponding author. Tel.: +1 908 740 2589.

cell growth, morphology, division, virulence, and importantly, blactam susceptibility of MRSA antibiotic resistance.8–11 Consequently, WTA biosynthesis provides an important new pathway of targets for considering antibacterial drug discovery, particularly from the perspective of a b-lactam combination agent strategy. TarO is the first enzyme involved in WTA biogenesis pathway. Inhibition of TarO does not cause bacterial death since the early-stage biosynthetic genes, such as tarO, are nonessential. Paradoxically, late stage WTA biosynthesis enzymes (e.g. TarG) are essential to the bacteria growth, but this essentiality can be reversed when the early stage enzyme, such as TarO, are inhibited in a late stage WTA defective strain background.10–14 In addition, depletion of WTA polymers confers resistance to bacteriophage (phage K) lysis. Accordingly, we used TarO biochemical activity, imipenem potentiation, Phage K lysis resistance, and TarG inhibitor (targocil) reversal assays to evaluate our synthetic compounds as WTA biosynthesis inhibitors targeting TarO enzyme.15 Compounds were prioritized based on the potency in all of these four assays. We previously reported the identification of a series of 2-cyclohexyl-benzimidazole analogs, tarocin B and 1, as WTA biosynthesis inhibitors, targeting TarO enzyme (Fig. 1).15,16 The initial lead 1 displayed a profile with nanomolar potency in TarO, phage K resistance, TarG inhibitor suppression and imipenem (IPM) synergy

E-mail address: [email protected] (S.-W. Yang). http://dx.doi.org/10.1016/j.bmcl.2016.08.036 0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

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S.-W. Yang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx

H

Br

H 2N

CO 2H

H 2N N

O

N

O

2

N O

H N N

N

N

N

5

Br c

N Br 4 MRSA COL alone >200 µM MRSA COL (+IPM ) MITC95 = 3 µM

>200 µM 0.004 µM

= 0.4 µM TarO assay: IC50 Phage K resistance EC50 = 3 µM TarG inhibitor suppression = 6 µM

<0.4 µM 0.027 µM 0.015 µM

cLogP

= 6.9

8

N

R1

N

R2

6 R 1 = Br, R 2 = H 1 R 1 = H, R 2 = Br

1

Tarocin B

N

O

3

a, b

N

O

d 6

N

Figure 1. Initial leads, tarocin B and 1, and their biological profiles.

N

7

9 R = CH 2OH, f rom e 10 R = CH 2N(CH3 )2 , from f

acid 8 was isolated as by-product

N

O

R

N

O

N

assays (Fig. 1). However compound 1 possessed high cLogP (8.0), and this might hinder its IV formulation when combined with IPM. Further work to enhance polarity of this series was therefore warranted by a SAR effort focused on installation of polar groups on different locations of the benzimidazole core and establishing the tolerability of the polar groups. The general method to prepare analogs 8–16 is shown in Scheme 1. The bromo intermediate (4) was obtained through amide coupling of 2 and 3, followed by cyclization under acetic acid condition. Bromo-imidazole 4 was coupled with acrylamide 5 through Michael addition to form regioisomers 1 and 6, which were separated. Bromo-replacement with an aldehyde group was achieved by heating a mixture of 6, Pd(OAc)2, cataCXium A, triethylamine, and NaOAc in toluene under Syngas (CO/H2, 100 psi). Acid 8 was also obtained in this step as a by product (20%). Standard reduction or reductive amination reaction was applied to 7 to yield target 9 or 10, respectively. Amide 11 was prepared from amide coupling of 8 and cyclopropanamine. Bromo-intermediate 6 was the subject of further Suzuki coupling reactions to generate arylated targets 12–16. The regio-selective synthetic route to the fluoro analogs 20–23 is summarized in Scheme 2. The reaction of fluoro substituted nitro-anilines 17 with intermediate 5 in neat sulfuric acid at 120 °C yielded intermediates 18. The nitro group of 18 was further reduced to an amino group using a hydrogen balloon (1 atm) and Pd/C as catalytic reagent. Intermediates 19 were the subject of further amide coupling reactions followed by internal cyclization in heated acetic acid to yield the desired targets 20–23. Replacement of the left-hand-side (LHS) cyclohexyl ring with a piperidinyl ring was also pursued, as shown in Scheme 3. Commercially available imidazole-piperidine 24 was directly coupled with 5 to form intermediate 25. The 6-fluoro regioisomer was also isolated from this step. However in this piperidinyl series, the profiles of 5-fluoro analogs were better than those of 6-fluoro analogs (data not shown). Therefore 6-fluoro analogs were not discussed here. The Boc group of 25 was removed by TFA to generate 26. Typical conversion of an amine to acetamide, urea, or carbamate was applied to piperidine 26 to afford targets 27–29. Phenyl-benzimidazole analogs 32–34 were prepared from 2-chloro-imidazole 30 through typical addition of 5, and Suzuki coupling reaction with various building blocks of boronic acids or esters (Scheme 4). Target compounds were tested for their activities in the TarO in vitro enzyme assay and the whole cell antibacterial cell assay with or without IPM. The active compounds were further tested in the phage K and Targocil reversal assays. The initial exploration focused on modifications of lead compound 1 with varying polar substitutions on the right-hand-side

N

O

e or f

N

O

g

O CO2 H

N

N

N

N H

N 11

8 12 R = Ph

6

13 R = 4-hydroxyl-Ph

N

O

h

14 R = 15 R =

R

N

N N N NH

16 R = N

OH

Scheme 1. Reagents and conditions: (a) HATU, Hunig’s base, DMF, rt; (b) AcOH, 120 °C; (c) K2CO3, DMF, 80 °C; SFC separation; (d) CO/H2, Pd(OAc)2, cataCXium A, Et3N, NaOAc, toluene, 100 °C, 100 psi, ratio of 7 to 8: 4:1; (e) NaBH4, THF, rt; (f) HN (CH3)2, NaBH(OAc)3, DCE, rt; (g) cyclopropanamine, HATU, Hunig’s base, DMF; (h) RB(OH)2, Pd(PPh3)4, K2CO3, ethanol, Mm, 120 °C.

O

F H2 N

O

N

a

b

F O2 N 17

HN

HN

O 2N

H2 N

18 c, d

N

F

19 N

O

F N N 20 - 23 Scheme 2. Reagents and conditions: (a) 5, H2SO4, 110–120 °C; (b) H2, Pd/C, MeOH, rt; (c) trans-4-ethylcyclohexane-1-carboxylic acid, HATU, Hunig’s base, DMF, rt; (d) AcOH, 90 °C.

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S.-W. Yang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx Table 1 SAR of substituted benzimidazole analogs

Boc

a

H N

N

N

N

O Boc

F

N

24

N

O

N N

F

N

7 R 6

25

5

N 4 c

N

O

b

N

O

R

TarO IC50 (lM)

COL MITC95 + IPM (4 lg/mL) (lM)

Phage K, EC50 (lM)

Targocil reversal EC50 (lM)

8 9

6-CO2H 6-CH2OH

147 0.1

200 0.5

>200 5.4

>200 7.1

10

6

N

200

25

>200

>200

6

H N

200

50

108

90

0.004

0.2

0.2

0.03

0.1

0.3

29

1.8

0.3

4.7

>200

>200

0.05

0.2

0.7

0.6

d HN

R

e

N N

N

N N

F

F

27 R = -Ac (from c) 28 R = -CONHEt (f rom d) 29 R = -CO 2Et (from e)

26

Scheme 3. Reagents and conditions: (a) 5, K2CO3, DMF, 120 °C; (b) TFA, CH2Cl2; (c) AcCl, Et3N, CH2Cl2, rt; (d) ethyl isocyanate, Et3N, CH2Cl2, rt; (e) ethyl chloroformate, Et3N, CH2Cl2, rt.

11 12

O 6-Phenyl

13

6

14

O H N

b

Cl N

N Cl

N R

N 30

N

O

a

31

OH 6 6

N N

16

6

N NH

20 21 22 23

4-F 5-F 6-F 7-F

15

N

OH

200

6.3

100

24

0.03 0.04 0.02 0.04

0.1 0.004 0.1 0.8

0.8 0.04 0.8 0.9

0.4 0.03 0.7 0.4

N 32-34

Scheme 4. Reagents and conditions: (a) 5, K2CO3, DMF, 120 °C; (b) RPh-B(OH)2 or RPh-boronic ester, Tetrakis, K3PO4, DMF/H2O, 100 °C.

(RHS) phenyl ring, and the results are summarized in Table 1. Carboxylic acid (8), tertiary amine (10), or amide (11) groups were not tolerated at 6-position. However, compound 9 with 6-hydroxylmethyl group exhibited a robust activity profile characteristic of WTA inhibitors. Installation of a hydroxyl group through a phenyl (13) or benzyl linker (14) was achieved, and only phenol 13 similarly showed a clear WTA inhibitor profile. Phenyl analog 12 was highly potent in all four assays, but the hydrophobic nature of the phenyl ring did not improve the physicochemical property. Two 6-pyrazole analogs (15 and 16) were prepared to address this issue, and only the methyl substituted 15 displayed a compelling WTA inhibition. The regio-selective syntheses allowed us to explore fluoro-substitution on 4- to 7-positions of the imidazole ring. All fluoro-substituted analogs (20–23) exhibited potent WTA inhibition. Compound 21 was especially potent in IPM potentiation assay against MRSA (MITC95 = 4 nM). In general only specific polar groups could be tolerated at 6-position. Compared with 1, compound 21 showed equal potent activities in the primary in vitro assays, improved physicochemical property (cLogP 7.0), and reduced molecular weight. To explore the tolerability of polar groups on the imidazole core, 2-ethyl-cyclohexyl group was replaced with a 3-piperidine ring. We observed that only carbamates can be tolerated on the nitrogen of the 3-piperidinyl core (25 and 29) in this study. Unsubstituted amine 26, amide 27, and urea 28 failed to display satisfactory WTA inhibitor properties. In general 3-piperidinyl analogs were more potent than those of 2- or 4-piperidinyl analogs (data not

shown). Although compounds 25 and 29 were not as active as 21 as WTA inhibitors, they displayed improved physicochemical property (cLogP 5.8 and 5.1, respectively). Phenyl-benzimidazoles 32–34 were prepared to explore the potential of cyclohexyl ring replacement with an aryl ring. Polar triazole ring (32) was not tolerated on 4-position of the LHS phenyl ring. However carboxylic methyl ester (33) or trifluoroethoxyl (34) group on 4-position of the LHS phenyl was tolerated for their WTA inhibitor profile. Even though 33 and 34 were not highly potent WTA inhibitors, they displayed improved hydrophilicity profile (cLogP 6.2 and 6.5, respectively). The identified WTA inhibitors were further evaluated in combination with IPM (4 lg/mL) for their antibacterial spectrum with against clinical isolates of MRSA and MRSE, shown in Table 4. Such combination showed 56–80% coverage against twenty five clinical MRSA isolates with MITC95 25 lM or lower concentrations. MRSE coverage of these compounds was also measured and was generally lower than MRSA coverage, except compound 23 (68% MRSA coverage vs 75% MRSE coverage). From this study, compounds 15, 20, 21, and 23 exhibited antibacterial coverage higher than 50% for both selected MRSA and MRSE clinical isolates. Compound 21 was selected for evaluation of pharmacokinetic (PK) study due to its highly potent synergistic effect with IPM (4 lg/mL) against MRSA COL (MITC95 4 nM) and its antibacterial coverage against MRSA (76%) and MRSE (54%) clinical isolates. Compound 21 possessed high rat plasma protein binding (100%). The rat PK assay was carried out with oral dosing at 2 mpk, and the Area Under Curve (AUC) value was measured over a 0–24 h duration. The PK study showed that 21 was bioavailable (F = 15%) with an AUC value of 0.9 lM h, moderate half-life (5 h), and slightly high clearance (12.8 mL/min/kg), as shown in Fig. 2.

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S.-W. Yang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx

N

O

MRSA COL alone MRSA COL (+IPM ) MITC95 =

>200 mM 0.004 mM

TarO assay: IC50 = Phage K resistance EC50 = TarG inhibitor suppression =

0.04 mM 0.04 mM 0.03 mM

cLogP

=

7

N

Rat plasma protein binding

N

Rat PK: half life = 5 h; Cl=12.8 mL/min/kg AUC = 0.9 mM*h; F=15%; at 2 mg/kg

F

100%

21 Figure 2. Biological and pharmacokinetic profile of 21.

Table 2 In vitro biological data of piperidinyl analogs.

R N

N N

25 26 27 28 29

Compound

%MRSAa

%MRSEa

9 12 13 15 20 21 22 23 25 29 33 34

68 72 56 80 68 76 68 68 64 68 64 68

ND 12 ND 67 58 54 42 75 4 ND ND 4

a percentage of MITC95 6 25 lM for 25 clinical MRSA or MRSE isolates when combined with IPM (4 lg/mL); ND: not determined.

N

O

Table 4 MRSA and MRSE coverage for selected WTA biosynthesis inhibitors

F

R

TarO IC50 (lM)

COL MITC95 + IPM (4 lg/mL) (lM)

Phage K, EC50 (lM)

Targocil reversal EC50 (lM)

CO2tBu H Ac CONHEt CO2Et

0.06 16.5 48 28 0.1

0.5 200 100 100 0.4

1.7 >200 >200 >200 3.3

1.5 >200 >200 >200 3.3

Among them, 5-fluoro analog 21 displayed the best synergistic antibacterial effect with MITC95 0.004 lM. From this study, we were also able to identify new subtypes of benzimidazole WTA biosynthesis inhibitors, such as piperidinyl-benzimidazole analogs (Table 2) and phenyl-benzimidazole analogs (Table 3). Several of these new WTA inhibitors (25, 29, 33, and 34) displayed improved hydrophilicity. Efforts on reducing cLogP of the original lead compound 1 led to the identification of comparable analog 21, which was used as a tool compound for further biological profiling. Compound 21 exhibited oral bioavailability (F = 15%) at 2 mpk in the rat PK model. The further biological evaluation of tool compound 21 will be discussed in due course. Acknowledgments

Table 3 In vitro biological data of the analogs with the LHS 4-substituted phenyl ring systems

N

O

The authors wish to acknowledge Dr. Daria Hazuda for her unwavering support and enthusiasm for early discovery antibacterial research at Merck & Co. The authors also thank Drs. Jim Tata and Emma Parmee for providing insight and support for this program, Mr. Deodialsingh Guiadeen for the preparation of 7 from 6, and the DMPK group for acquiring pharmacokinetic data. References and notes

N R N

32 33 34

R

TarO IC50 (lM)

COL MITC95 + IPM (4 lg/mL) (lM)

Phage K, EC50 (lM)

Targocil reversal EC50 (lM)

4 N

3.8

19

>200

>200

0.1 0.04

1.2 0.3

6.9 1.2

4.3 1.1

N N –CO2CH3 –OCH2CF3

In conclusion, further exploration of the benzimidazole series was expanded. Some novel benzimidazole analogs with various substitutions on the RHS phenyl ring (Table 1) and ethyl-cyclohexyl ring replacement (Tables 2 and 3) were prepared. The SAR studies based on TarO, phage K, TarG inhibitor reversal, as well as synergistic antibacterial effect against methicillin-resistant Staphylococci were established. Intention of installing polar groups (e.g. hydroxyl or pyrazole group) led to new WTA inhibitors 9, 13, and 15. However the synergistic antibacterial effects of these compounds were less potent than that of 1. Mono-fluoro substitution on the RHS phenyl ring was tolerated at all positions (20–23).

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