Abstract
Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure–activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.
Keywords: Tuberculosis, type II topoisomerases, DNA gyrase, NBTIs, aminopiperidines, benzimidazoles
Tuberculosis remains a major public health problem across the world and claims approximately 1.5 million lives each year.1 The current treatment regimen involves a combination of four drugs administered for six months. The emergence of multidrug resistant (MDR) forms of Mycobacterium tuberculosis (Mtb) has further aggravated the situation, and individuals with MDR-TB require treatment with a cocktail of 6–8 drugs over an extended period of up to 24 months.2
DNA gyrase, a type II toposiomerase responsible for DNA replication and repair, is essential in all bacteria including mycobacteria and absent in eukaryotes. The enzyme catalyzes the interconversion of various topological forms of DNA, an essential process in DNA replication. It introduces negative supercoiling into circular DNA in an ATP-dependent reaction. This enzyme is a heterotetramer comprising of GyrA and GyrB subunits (A2B2). The GyrA subunit contains the DNA breakage-reunion site, while GyrB hydrolyses ATP to generate the energy required for enzyme activity. Unlike most other bacteria, Mtb has a functional DNA gyrase but no topoisomerase IV enzyme. There are at least two types of gyrase inhibitors reported in the literature with potent activity against Mtb. The first type of inhibitors target the ATP recognition site of GyrB enzyme and block ATP hydrolysis. Examples of this type are aminopyrazinamides, thiazolopyridine ureas, and pyrrolamides.3,4 The second type of inhibitors target the GyrA subunit thereby inhibiting the DNA breakage–reunion function of the enzyme. This class is exemplified by the fluoroquinolones (FQ), novel bacterial topoisomerase inhibitors (NBTIs) and aminopiperidines.3,4
The approval of FQ such as ofloxacin and moxifloxacin to treat several bacterial infections validates DNA gyrase target for the development of newer antibacterial agents. Several studies have shown the clinical benefit of FQs such as ofloxacin and moxifloxacin in the treatment of TB.5 However, reports of Mtb strains resistant to FQs pose a threat to the continued use of this class of drugs to treat TB.5 Therefore, identification of a novel GyrA inhibitors with unique binding mechanism that is distinctly different from the binding mode of the FQ class is needed. This would lead to the discovery of novel gyrase agents that can act against FQ resistant Mtb strains.
In the recent past, numerous NBTIs have been reported in the literature as antibacterial and antimycobacterial agents.3,4 The crystal structure of a Staphylococcus aureus DNA gyrase bound to one of the NBTI provides insight into the unique binding mechanism of this class of compounds and highlights the key interactions involved in the gyrase active site, which are nonoverlapping to the binding site of FQs. This unique interaction in turn confers the ability of NBTIs to retain their activity against FQ-resistant strains of S. aureus.6
In general, the NBTIs consists of a quinoline or naphthyridine based left-hand side (LHS) ring, a mono- or bicyclic hydrophobic right-hand side (RHS) ring and a linker joining the RHS and LHS in a proper orientation. Many NBTIs with variations in the LHS, linker and RHS with antibacterial and antimycobacterial activity have been reported. This includes the N-linked aminoperidines with both monocyclic and bicyclic RHS (1a-e),3,4N-cyclobutyl piperdine-3-carboxylic acid (1f),8 tetrahydropyran (1g),9 and oxabicyclooctane (1h) (Figure 1).10
Figure 1.
Novel type II topoisomerase inhibitors reported in the literature.
The aminopiperidine-based NBTIs with both monocyclic and bicyclic RHS (1a–1g) have shown in vitro activity against Mtb and also been shown to retain their activity against FQ-resistant strains of Mtb. In addition, this class of compounds were found to be efficacious in a murine model of tuberculosis.4,7 However, inhibition of the cardiac ion channel (hERG) remains a serious liability for the aminopiperidine based NBTIs with monocyclic RHS. In order to identify a scaffold with novel RHS group, we embarked on a scaffold hopping approach based on the literature reported aminopiperidines and its bound crystal structure with the S. aureus DNA gyrase (Figure 2). Herein, we report the discovery of a novel class of benzimidazoles (5 and 6, Figure 2), which inhibits Mtb DNA gyrase with potent antimycobacterial activity. These compounds are bactericidal and retain their minimum inhibitory concentration (MIC) against FQ-resistant strains of Mtb. The identified structure–activity relationship (SAR) for hERG mitigation provides an attractive opportunity to further optimize the benzimidazole lead toward preclinical candidate selection.
Figure 2.
Scaffold hopping of NBTIs.
The syntheses of compounds with piperidine linkers are described in Scheme 1.
Scheme 1. Synthesis of Benzimidazoles.
Reagents and conditions: (a) CsCO3, DMSO, 90 °C; (b) NaOMe, MeOH, 75 °C; (c) mesyl chloride, DIPIEA, DCM, 0 °C; (d) PTSA, ethanol, 90 °C; (e) 4 N HCl in dioxane, 50 °C; (f) Na2CO3, DMF, 130 °C.
Alkylation of LHS ring (2a–c) with 2-bromoethanol in the presence of cesium carbonate as a base provided N-alkylated product (3a–d) as the major isomer. Nucleophilic displacement of 3a with sodium methoxide in methanol under heating conditions resulted in intermediate 3b. The mesylates (4a–d) were obtained by treating 3a–d with mesyl chloride under basic conditions. The mesylates (4a–d) were freshly prepared and used immediately for the next step due to potential instability reasons. The N-BOC protected piperidinyl benzimidazoles (6a–f) were synthesized by treating corresponding ortho-phenylenediamines (5a–f) with N-BOC piperidine-4-carboxaldehyde (24) in the presence of para-toluene sulfonic acid (catalytic amount) under open air conditions. The secondary piperidines (7a–f) were obtained upon deprotection of N-BOC group under acidic conditions. Alkylation of secondary piperidines (7a–f) with mesylates (4a–d) in the presence of Na2CO3 as base under thermal heating conditions resulted in the title compounds (5 and 9–18).
Treatment of mesylate 4a with N-BOC protected piperazine (8b) under basic condition and heating provided 9a (Scheme S2, Supporting Information). Intermediate 9b was obtained from 9a using sodium methoxide. Alkylation of secondary piperazines (7a–g) with 2-choro benzimidazoles (11a–c) in the presence of a base under microwave conditions resulted in the title compounds (6–8 and 19, Scheme S2, Supporting Information). Compounds 2, 3, and 4 were synthesized as per Schemes S4 and S5 (Supporting Information). Nucleophilic displacement of fluoro naphthyridones (8 and 10) with pyridinol (12a) or phenol (12b) or using cesium carbonate under thermal heating conditions resulted in the title compounds 21–23 (Scheme S3, Supporting Information).
Scaffold Hopping and Hypothesis Generation
Toward identifying a structurally distinct novel mycobacterial gyrase inhibitor, we attempted scaffold hopping of NBTIs. The binding mode of NBTIs from the published crystal structures revealed that the linker −NH group and the RHS part of NBTIs (GSK299423, 1e, Figure 3a)6 makes a critical interaction in the protein. So we have focused our scaffold morphing efforts toward designing of new compounds with novel RHS (compounds 2–6, Figure 2). We hypothesized that constraining the NH of amino piperidine based NBTIs as part of a bicyclic ring should provide access to the hydrogen bonding interaction with Asp83 (Asp89 in the case of Mtb gyrase) as observed in the NBTI bound crystal structure of S. aureus DNA gyrase (PDB ID: 2XCS). To validate this hypothesis, we designed compounds with benzimidzole (5 and 6, Table2), indole (2 and 3, Table 1), and oxindoles (4, Table 1) as novel RHS (Figure 2).
Figure 3.
(a,b) Docking pose of compounds 5 (cyan), 4 (pink), 3 (orange), and 2 (yellow) on to the crystal bound structure of GSK299423 (green) to S. aureus DNA gyrase.6 (c) Docking pose of compound 5 on to the homology model of Mtb DNA gyrase subunit A. (d) Docking pose of compound 23 on to the homology model of Mtb DNA gyrase subunit A.
Table 2. SAR Modifications around the RHS and LHS Part of Benzimidazoles.
Not determined.
Table 1. Profile of Compounds with Novel RHS.
| entry | MIC Mtb H37Rv (μM) | Mtb gyrase SC IC50 (μM) | Msm GyrB ATPase IC50 (μM) | cytotoxicity THP-1 IC50 (μM) | hERG IC50 (μM) | logD pH 7.4 |
|---|---|---|---|---|---|---|
| 2 | 100 | >50 | >100 | >50 | 2 | 3.3 |
| 3 | 50 | >50 | >100 | >50 | 1.8 | 4 |
| 4 | 100 | >50 | >100 | >50 | 4.8 | 2.8 |
| 5 | 0.19 | 1.0 | >100 | >50 | 1.0 | 4 |
The newly designed compounds 2, 3, 4, and 5 were docked into 2XCS and a Mtb DNA gyrase subunit A (Mtb GyrA) homology model to understand the binding interactions. Figure 3 depicts the possible binding modes of compounds 2, 3, 4, and 5 in the S. aureus DNA bound GyrA subunit and in the Mtb GyrA model (Figure S7 in Supporting Infromation). The H-bonding contacts with Asp83 (Asp89 in the case of Mtb GyrA model) and hydrophobic pocket occupied by Ala68, Val71, Gly72, and Met121 of S. aureus DNA bound GyrA (Ala74, Val77, Ala78, and Met127 in Mtb GyrA, respectively) were key interactions in the NBTIs binding site. The binding mode for benzimidazole derivative 5 suggests that the hydrogen of N-1 atom of benzimidazole ring is engaged in H-bonding interaction with the carboxylate of Asp83 (Asp89 in the case of Mtb GyrA model) and CF3 group attached to C-5 position point toward the hydrophobic pocket. This is similar to the interactions observed for NBTIs. Thus, compound 5 is likely to be active against Mtb gyrase. However, the ring NH group in compounds 2, 3, and 4 is not suitably placed to make the desired hydrogen bonding interaction with Asp 83 (Asp89 in the case of Mtb GyrA model) due to the adaptation of a different conformational orientation of indole (2 and 3) and oxindole (4) rings in comparison to benimidazole ring (5). Furthermore, the substituent attached to C-5 or C-6 position of bicylic rings in compounds 2 and 4 is likely to be pointing away from the hydrophobic pocket constituting Ala68, Val71, Gly72, and Met121 of S. aureus GyrA (Ala74, Val77, Ala78, and Met127 in Mtb GyrA, respectively). The CF3 group attached to C-6 in compound 3 is likely to pick up the hydrophobic interaction. In all cases, the naphthyridone ring assembled between the two base pairs of DNA, similar to the reported binding mode of NBTIs.
On the basis of these observations, we synthesized compounds 2–5 with different RHS and tested for Mtb gyrase inhibition. The biological activities, in vitro safety, and logD of these novel leads are shown in Table 1.
Compound 5 with benzimidazole RHS inhibited Mtb DNA gyrase supercoiling in the single-digit micromolar range and displayed potent MIC against Mtb. Compounds 2, 3, and 4 with indole and oxindole RHS, were inactive against the enzyme (IC50 > 50 μM) and showed weak Mtb MIC (50–100 μM). As predicted by docking studies, compounds 2–4 are expected to be inactive against the Mtb gyrase, as these compounds are unable to pick up the critical interaction with Asp89. Hence, the observed lack of Mtb gyrase inhibition for compounds 2–4 is in agreement with the results from the docking studies. In order to rule out any contribution of Mtb GyrB inhibition to the observed Mtb MICs, compounds were screened against Mycobacterium smegmatis (Msm) GyrB as a surrogate for Mtb GyrB enzyme.3 The lack of inhibitory activity of compounds 2, 3, 4, and 5 against the Msm GyrB clearly indicated that these compounds were inhibitors of either the holoenzyme (GyrA2B2 complex) or GyrA subunit. In addition, these compounds showed no signs of cellular cytotoxicity (IC50 > 50 μM) against a human monocytic cell line (THP1), thereby demonstrating excellent selectivity. However, these compounds showed potent hERG inhibition at single digit micromolar range (hERG IC50 1 to 4.8 μM, Table1), likely due to higher lipophilicity (logD = 2.8 to 4) observed with the initial set of compounds synthesized in this study.
Encouraged by the potent Mtb activity observed for compound 5, we envisaged the SAR requirements for the newly identified benzimidazole RHS and we used MIC as an activity indicator to track the SAR. We assumed that the mechanism of gyrase inhibition was similar across the newly synthesized compounds with benzimidazole RHS. Piperidine-based linker was found to be optimal for Mtb MIC. A substitution of piperidine with piperazine led to the weakening of Mtb MIC by 15-fold (compound 5 versus 6, Table 2). Removing the R2 substitution at the C-5 position of benzimidazole resulted in the loss of Mtb MIC by 25-fold, thereby proving the essentiality of hydrophobic group at the C-5 position (compound 6 versus 7, Table 2). Similarly, changing OCH3 to F at R1 position of LHS resulted in the loss of Mtb MIC by 4–8-fold, suggesting that a bulky substitution may be essential for the MIC activity (7 versus 8, 5 versus 9, 10 versus 12, and 14 versus 15 as match pairs, Table 2). As suggested by modeling studies, the RHS benzimidazole-binding region was more hydrophobic in nature; additionally the electron withdrawing hydrophobic groups such as CF3 strengthens the H-bonding interaction of ring NH with Asp 89. In order to expand the hydrophobic pocket SAR further, we varied R2 substitutions at the C-5 and introduced an R3 substitution at C-6 position of benzimidazole RHS. Replacement of CF3 group by Cl at the C-5 position retained the Mtb MIC (compound 5 versus 11), whereas CN substitution weakened MIC by 20-fold (compound 5 versus 12). This data suggests that the electron withdrawing hydrophobic group at the C-5 position is essential for conferring potent Mtb MIC for this series. Introduction of other hydrophobic substituents such as methyl or fluorine enhanced the potency by 4-fold (compound 11 versus 13 and 14, Table 2). The addition of a nitrogen at the 8 position of LHS ring as pyrido[2,3-b]pyrazin-2(1H)-one (compound 16) or moving nitrogen to 4-position of LHS as 1,4-quinoxazolinone (compound 17) was broadly tolerated for potency. Compound 17 showed moderate improvement in reducing hERG inhibition (hERG IC50 10 μM against 1.4 μM for compound 14). This could be due to a slight reduction in logD or disturbance of pi-stacking of the LHS group to the hERG channel. Furthermore, changing Cl to CN at the C-5 position of benzimidazole RHS with both piperidine and piperazine linker retained the Mtb MIC but showed >4-fold improvement in mitigation of hERG (14 versus 19 and 20, Table 2). The mitigation of hERG liability observed for compounds 19 and 20 may be due to lowered logDs and disturbing the pi-stacking interaction of the RHS group to the hERG channel.
To expand the SAR scope of R1 group at LHS and improve hERG selectivity, we explored suitably substituted aryl rings at R1 of LHS that can lower logD. Initially, introduction of 3-pyridyloxy at R1 instead of OCH3 retained Mtb MIC but did not show any improvement in reducing hERG liability. Replacement of 3-pyridyloxy by 4-phenoxy sulphonamide at R1 position of LHS showed excellent improvement in Mtb MIC and hERG mitigation (compound 21 versus 22 and 23, Table 2). This suggested that polar bulky substitution at R1 position may not disturb the binding orientation of NBTIs as evident from the docking pose of 23 in Mtb GyrA homology model (Figure 3d). Further exploration of this trend with various combinations of RHS will be presented. In order to link whole cell potency to Mtb gyrase inhibition, representative compounds (5, 6, 13, 14, 19, and 23) were tested in the Mtb DNA gyrase supercoiling assay (Table 3). Most of the compounds with MIC against Mtb also inhibited supercoiling activity of Mtb gyrase thus confirming their mode of inhibition.
Table 3. Activity of Benzimidazoles against Mutants Resistant to Compounds 1a, 1d, or Moxifloxacin.
| MIC (μM) |
|||||
|---|---|---|---|---|---|
| entry | Mtb gyrase SC IC50 (μM) | Mtb H37Rv wild-type | Compd 1aR mutant (A74V) | Compd 1bR mutant (D89N) | MoxiR mutant (G88N) |
| 1a | 0.11 | 0.19 | 4 | >100 | <0.19 |
| 1c | 0.25 | 0.19 | 2 | >100 | <0.19 |
| 5 | 1.0 | 0.19 | 50 | 25 | 0.78 |
| 13 | 2 | 0.03 | 100 | 25 | 0.06 |
| 19 | 4.3 | 0.19 | >100 | 100 | 0.78 |
| 20 | NDa | 0.78 | >100 | 100 | 1.56 |
| 23 | 1.9 | 0.19 | 25 | 12.5 | 0.39 |
| moxifloxacin | 12.5 | 0.13 | 0.25 | 2 | 4 |
| ciprofloxacin | NDa | 0.5 | 0.5 | 16 | 8 |
| isoniazid | NDa | 0.06 | 0.06 | 0.03 | 0.06 |
| rifampicin | NDa | 0.015 | 0.008 | 0.015 | 0.008 |
Not determined.
In order to differentiate benzimidazoles from FQs and NBTIs, compounds (5, 6, 13, 14, 19, and 23) were screened against moxifloxacin and NBTI-resistant mutant of Mtb (1a and 1b mutants).4 These compounds retained their MIC against lab derived moxifloxacin-resistant mutant, but lost their activity against a NBTI-resistant mutant by >25-fold. This result indicates that this class of molecules is likely to be effective against FQ-resistant strains of Mtb and that the mechanism of inhibition is similar to that reported for other NBTIs.
The representative compounds (19 and 20) were evaluated for their activity against a panel of cytochrome P450 isozymes (CYP) and in vivo pharmacokinetics profile in rats (Table S4, Supporting Information). Compounds 19 and 20 did not inhibit CYP isozymes up to 20 μM, except against CYP3A4 enzyme (IC50 of 9.5 μM for 19).
Compounds 19 and 20 exhibited low to moderate in vivo clearance, low volume of distribution, and short half-life in rats. Oral bioavailability was found to be very low (1 to 3%) for both compounds despite low to moderate clearance (Table S4, Supporting Information). This could be due to poor oral absorption associated with low solubility and poor intestinal permeability of these compounds.
In conclusion, we have described the discovery of benzimidazoles as novel gyrase inhibitors with potent Mtb MIC and with a similar mechanism as that of NBTIs. Introduction of polar groups at the C-7 position of LHS provided avenues for building selectivity SARs against hERG. Further efforts are required to optimize PK parameters and to assess in vivo safety. We believe that this class of compounds has potential to be developed as anti-TB drug candidate.
Acknowledgments
Our sincere thanks to Drs. T. Balganesh, B. Ugarkar, Pravin Iyer Balasubramanian, and Shridhar Narayanan for their valuable suggestions and encouragement during the course of this work. We aslo thank CMG Bangalore, AZ Global DMPK, Safety, Biosciences (AZ Boston, USA), and Discovery Sciences (AZ, Alderly Park, UK) for technical support in various assays
Supporting Information Available
Computational methods; determining the antimycobacterial properties; determination of IC50 for the supercoiling activity of M. tuberculosis H37Rv gyrase holoenzyme; determination of resistance frequency; genetic mapping of mutations conferring resistance to N-linked aminopeperidinyl alkyl quinolones and naphthyridones; assay procedures for log D and hERG measurement; DMPK profile for benzimidazoles; sythetic schemes and procedures. This material is available free of charge via the Internet at http://pubs.acs.org.
Author Present Address
‡ (D.S.) BITS-Pilani, Hyderabad Campus, Shameerpet, Hyderabad 500 078, India.
Author Contributions
S.H.P., V.S., A.R., P.M., and S.D. wrote the manuscript and participated in the design and execution of this study. S.H.P. performed the chemical syntheses. S.S., R.N., J.R., P.V., and P.K. performed and interpreted biological data. S.M. performed the analytical experiments to assign the structure of newly synthesized compounds.
The authors declare no competing financial interest.
Supplementary Material
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