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. 2014 Aug 15;5(10):1133–1137. doi: 10.1021/ml500279k

Synthesis and Structure–Activity Relationships of α-Amino-γ-lactone Ketolides: A Novel Class of Macrolide Antibiotics

Dražen Pavlović †,*, Stjepan Mutak †, Daniele Andreotti ‡, Stefano Biondi ‡, Francesca Cardullo ‡, Alfredo Paio ‡, Elisa Piga ‡, Daniele Donati ‡, Sergio Lociuro ‡
PMCID: PMC4190632  PMID: 25313326

Abstract

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An efficient synthesis of α-amino-γ-lactone ketolide (3) was developed, which provided a versatile intermediate for the incorporation of a variety of aryl and heteroaryl groups onto the C-21 position of clarithromycin via HBTU-mediated amidation. The biological data for this important new class of macrolides revealed significantly potent activity against erythromycin-susceptible strains as well as efflux-resistant and erythromycin MLSB-resistant strains of S. pneumoniae and S. pyogenes. In addition, ketolide 11o showed excellent in vitro antibacterial activity against H. influenzae strain as compared to telithromycin. These results indicate that C-21 substituted γ-lactone ketolides have potential as a next generation macrolide antibiotics.

Keywords: Macrolide antibiotics, macrolide resistance, ketolides, structure−activity relationships

Historically, new generations of macrolides have been produced by synthetic modification of existing macrolide core structures.1−3 Efforts culminated in the late 1980s with the commercialization of clarithromycin4 and azithromycin,5 but these compounds remain ineffective against many of the macrolide-resistant pathogenic strains.6 Discovery of ketolides, exemplified by telithromycin (1)7 and cethromycin (ABT-773; 2),8 represented a breakthrough in macrolide structure–activity relationships (Figure 1). Structurally, the ketolides are semisynthetic derivatives of erythromycin A characterized by the presence of a 3-keto group in place of the l-cladinose moiety and an alkyl-aryl extension at the positions 11 and 12 of the cyclic carbamate ring.

Figure 1.

Figure 1

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Representative examples of ketolides and novel C-21 substituted γ-lactone ketolides derived from 14-membered macrolides.

Most of the ketolides developed after original disclosure of telithromycin contain a cyclic carbamate fused to C-11 and C-12 of the macrocyclic core.9 Besides cyclic carbamates, C-11/C-12 cyclic urea,10 thiocarbamate,11 and carbazate analogues12 were also recently synthesized. Our efforts in this area were directed toward the design, synthesis, and functionalization of a new series of ketolides that contain γ-lactone ring fused to C-11 and C-12 position of the clarithromycin scaffold. Although basic unsubstituted13,14 and arylalkylthio-γ-lactone scaffold15 were recently synthesized, further efforts directed toward efficient diversification of these important intermediates remain scarce. In addition, researchers at Johnson and Johnson disclosed a novel series of ketolides containing C-6 substituted heteroaryl side chain and C-11/C-12 γ-lactone functionality.16 In particular, we have developed a new series of γ-lactone ketolides modified at the C-21 position of the lactone ring with an α-amino group, which was further functionalized with an aromatic or heteroaromatic side chain (Figure 1, 3 and 4). α-Amino lactone derivative of clarithromycin (3) was chosen as a key intermediate for the introduction of appropriate aryl or heteroaryl side chain because it represents novel proprietary scaffold suitable for straightforward chemical derivatization via N-acylation chemistry.17 It was hypothesized that the diversification at C-21 carbon atom of the γ-lactone ring with a variety of heterocyclic side-chain appendages similar to those found in our recent paper18 would result in enhancement of antibacterial activity against resistant pathogens. In this letter, we describe the synthesis and biological properties of C-21-substituted clarithromycin ketolides, as a novel class of macrolide antibiotics, which show good antibacterial activity against Gram-positive pathogens including a macrolide-lincosamide-streptogramin B (MLSB) and efflux-resistant strains of S. pneumoniae and S. pyogenes.

As part of the research program aimed at discovering next generation macrolide antibiotics active against multidrug-resistant respiratory pathogens, we have investigated a broad range of 14- and 15-membered ring macrolides.19,20 This project was directed toward the development of an efficient synthetic methodology to access α-amino lactone ketolides, a novel class of 14-membered ketolide antibiotic with significant in vitro potency against macrolide-resistant strains. The synthetic route for accessing a basic α-amino lactone scaffold (3) as a convenient point of attachment for rapid structure–activity relationship (SAR) exploration (Scheme 1) rests on stereoselective incorporation of the α-amino lactone moiety via an intramolecular Michael addition. Central to this strategy is the creation of a suitably oriented C-21 α-amino group attached on the γ-lactone moiety via a stereoselective intramolecular Michael addition. This amino group provides a handle to introduce novel aryl and heteroaryl moieties (Chart 1) directly onto the C-21 position of the macrolide core via HBTU-mediated amidation.

Scheme 1. Synthesis of 21-Amino-2′-O-acetyl-3-O-descladinosyl-11,12-dideoxy-6-O-methyl-12,11- (oxycarbonylmethylene)-3-oxo-erythromycin A (3) Followed by HBTU Coupling.

Scheme 1

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Reagents and conditions: (a) BocGly, EDC·HCl, DMAP, CH2Cl2, r.t., 80%; (b) TFA, CH2Cl2, 0 °C to r.t., 90%; (c) Ph2CNH, Et3N, CH3CN, reflux, 90%; (d) DBU, CH3CN, reflux, 80%; (e) LiOH·H2O, CH3CN, r.t., 90%; (f) 1 M HCl, CH3CN, r.t., 80%; (g) LiOH·H2O, CH3CN, r.t., 80%; (h) RCO2H, HBTU, DIPEA, DMF, r.t., 50–90%; (i) MeOH, r.t., 95%.

Chart 1. Aryl and Heteroaryl Scaffolds Used as the R Substituents in HBTU Coupling of 3.

Chart 1

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The α,β-unsaturated ketone 5 used as a starting material for the preparation of α-amino lactone (3) was prepared by modification of the published procedure.21 The synthesis of key intermediate 3 began with selective acylation of C-12 hydroxyl group by tert-butyloxycarbonyl (Boc) glycine in the presence of 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (EDC·HCl) and the catalytic amount of DMAP (Scheme 1).

The 12-O-Boc glycyl derivative 6 thus obtained was subjected to selective deprotection of the Boc group by exposure to trifluoroacetic acid in dichloromethane at room temperature. Acylation of 5 with chloroacetyl chloride or mixed acid anhydride (ClCH2CO2H, PivCl, Et3N, DMAP, CH2Cl2, −15 °C to room temperature) led to reduced yields (30–50%) and was consequently not explored further.

The crystalline ammonium salt 7 was isolated in 90% yield and allowed to react with benzophenone imine to afford the precursor 8 used in the crucial intramolecular Michael addition. Following column chromatography on silica gel benzophenone imine analogue 8 was subjected to DBU-mediated Michael addition in acetonitrile at reflux to afford γ-lactone intermediate 9a/b as an inseparable mixture of diastereoisomers at C-10 carbon atom (ratio C10-(R)/(S) = 8/2). Base-catalyzed isomerization of 9a/b in the presence of lithium hydroxide monohydrate allowed the epimerization at the C-10 position to the desired C10-(R) diastereisomer 9a in 80% yield. Deprotection of benzophenone imine 9a in aqueous hydrochloric acid provided α-amino-γ-lactone intermediate 3 that was subsequently used in HBTU-mediated coupling reactions.

When LiOH was used instead of DBU only one diastereoisomer was observed according to LC/MS analysis of the crude reaction mixture. Thus, upon exposure to LiOH, 8 underwent an intramolecular Michael addition to give exclusively C10-(R) diastereoisomer 9a. The configuration at C-10 was confirmed by coupling constants in 1H NMR spectrum of deprotected analogue 9 (2′-OH, Supporting Information, page S24) suggesting that the 10(R)-epimer was indeed formed exclusively.22 Acid hydrolysis of benzophenone imine 9a with 1 M HCl in acetonitrile again provided α-amino-γ-lactone ketolide (3) with the spectral data that were identical to the sample isolated after base-catalyzed isomerization of the diastereoisomeric mixture 9a/b followed by acid hydrolysis of 9a.

Coupling of various aryl and heteroaryl carboxylic acids (Chart 1) with α-amino lactone ketolide 3 was carried out in DMF with hydroxybenzotriazole uronium salt (HBTU) in the presence of diisopropylethyl amine (DIPEA) in generally acceptable isolated yields ranging from 50 to 90% (Scheme 1).

Deprotection of the 2′-acetyl group on cladinose was readily accomplished by stirring in methanol at room temperature to give essentially quantitative yield of C-21 functionalized α-amino lactone ketolides (11a–p). Many of the carboxylic acids used for HBTU coupling reaction were either commercially available or synthesized using well-precedented chemistries.7

The synthesis of quinoxaline carboxylic acid 14, however, had to be developed from more basic building blocks as illustrated in Scheme 2. Therefore, quinoxalin-2-yl thioacetic acid 12 was treated with methyl ester of glycin hydrochloride in the presence of HBTU as a coupling reagent and DIPEA for 2 h at room temperature (Scheme 2). Subsequent hydrolysis of the glycine ester 13 was carried out with lithium hydroxide in THF/water mixture (1:1) at room temperature. This procedure afforded almost quantitative yield of the corresponding carboxylic acid 14 after acidic workup at pH = 4.

Scheme 2. Synthesis of Quinoxalin-2-yl Thioacetyl Glycine 14.

Scheme 2

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Reagents and conditions: (a) HBTU, DIPEA, DMF, r.t., 85%; (b) LiOH·H2O, THF/H2O (1:1), r.t.; 2 M aq. HCl, pH = 4, 95%.

The antibacterial activity of the C-21 substituted α-amino-γ-lactone ketolides was tested against a panel of representative pathogens selected from Pliva Research Institute culture collection. The in vitro antibacterial activities are reported as minimum inhibitory concentrations (MICs) that were determined by the agar microdilution method according to NCCLS standards.23 Table 1 shows the in vitro activity of the ketolide analogues and the reference compounds, azithromycin, telithromycin (1), and cethromycin (2).

Table 1. In Vitro Antibacterial Activity of C-21-α-Amino-γ-lactone Ketolides against Selected Pathogensa.

  S. aureus
 S. pneumoniae
 S. pyogenes
  
compd Ery-S iMLS MLSB Ery-S MLSB M Ery-S MLSB M H. influenzae
3ab 1 32 >64 ≤0.125 >64 8 2 >64 8 >64
11a 4 8 >64 ≤0.125 16 4 0.5 16 8 16
11b 4 8 >64 ≤0.125 16 8 ≤0.125 2 2 2
11c 2 4 >64 ≤0.125 4 2 ≤0.125 4 2 8
11d 4 4 >64 ≤0.125 2 2 ≤0.125 32 4 16
11e 1 1 >64 ≤0.125 2 2 ≤0.125 4 8 2
11f 1 1 >64 ≤0.125 1 0.5 ≤0.125 1 2 4
11g 0.5 1 >64 ≤0.125 0.25 0.25 ≤0.125 0.5 0.25 1
11h 2 1 >64 ≤0.125 0.5 0.5 ≤0.125 0.25 0.5 1
11i 2 2 >64 ≤0.125 8 1 ≤0.125 8 4 8
11j 1 1 >64 ≤0.125 2 2 ≤0.125 0.5 2 1
11k 2 2 >64 ≤0.125 8 4 ≤0.125 0.25 4 1
11l 1 2 >64 ≤0.125 8 4 ≤0.125 8 16 16
11m 1 1 >64 ≤0.125 2 4 ≤0.125 4 4 16
11n 1 2 >64 ≤0.125 4 4 ≤0.125 2 4 8
11o ≤0.125 0.25 >64 ≤0.06 ≤0.125 0.25 ≤0.06 0.25 0.25 0.5
11p ≤0.125 0.25 >64 0.25 0.5 0.5 0.25 1 0.5 2
Azi 1 >64 >64 ≤0.125 >64 4 ≤0.125 >64 1 1
1 ≤0.125 0.5 >64 ≤0.06 ≤0.125 0.5 ≤0.06 4 0.25 2
2 ≤0.125 0.25 >64 ≤0.06 ≤0.125 ≤0.06 ≤0.06 1 ≤0.125 2
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a

Minimum inhibitory concentration (MIC) values are given in μg/mL. Ery-S, erythromycin-susceptible strains; iMLS, inducibly resistant strains; MLSB, constitutively resistant strains; M, efflux-resistant strains; Azi, azithromycin.

b

Compound 3a (2′-OH) was synthesized by deprotection of compound 3 (2′-OAc) in MeOH at room temperature.

The basic, deprotected α-amino-γ-lactone scaffold 3a exhibited excellent activity against the susceptible strain of S. pneumoniae, moderate activity against the efflux resistant strains, but very poor potency against constitutively MLSB-resistant S. pneumoniae and S. pyogenes. The antibacterial profile of 3a is not unexpected knowing the well-established need for an aromatic or heteroaromatic ring attached to the macrolide scaffold as a necessary requirement for potent antibacterial activity against constitutively MLSB-resistant strains. In general, the ketolides were also inactive against constitutively MLSB-resistant strain of Staphylococcus aureus (MIC > 64 μg/mL). In contrast, most of the C-21 substituted γ-lactone ketolides were active against inducibly resistant S. aureus strains. The most interesting feature of these new compounds was their effectiveness against efflux resistant S. aureus and S. pneumoniae strains as well as constitutively MLSB-resistant S. pneumoniae and S. pyogenes. The compounds generally maintained good activity against both, the erythromycin-susceptible and MLSB constitutively resistant strains of S. pyogenes and S. pneumoniae.

Attachment of a simple benzyl substituent (11a) resulted in dramatic improvement of antibacterial activity against constitutively MLSB-resistant S. pneumoniae and S. pyogenes. The activity against efflux- and constitutively MLSB-resistant strains was further improved with the corresponding pyridylethyl analogues (11b, c, and d). In terms of the site of attachment within the pyridine analogues, positions 2 and 3 appear to be optimal for the S. pneumoniae (MLSB) activity, whereas for H. influenzae and S. pyogenes (MLSB) activity position 4 appears to be preferred.

The rest of the analogues presented in Table 1 cover fused bicyclic aryl- and heteroaryl-systems (11e–p). In reviewing the SAR data of these analogues, it is evident that compounds containing fused bicyclic aryl- and heteroaryl-rings (11e–p) generally possessed a better overall antibacterial profile than simple monoaryl (16a) and monoheteroaryl systems (11b–d). The quinolyl analogue (11f), for example, demonstrated improved activity when compared to its monoaryl and monoheteroaryl counterparts 11a and 11c, respectively. In addition, the overall activity spectrum of C-21 substituted γ-lactone ketolides can be improved by the nature and length of the tether connecting heteroaryl ring and the macrolide core. It is a common knowledge that the length of the tether connecting heterocycle and the macrolide is critical for the antibacterial activity, and a four-carbon alkyl chain appeared to be optimal when the tether is attached at the C-11 carbamate nitrogen.7 In addition to linear alkyl chains, amine-, hydrazine-, amide-, olefin-, and ether-containing linkers have been disclosed.7,24,25 Most of the linkers used in this work contain four atoms between the aryl- or heteroaryl-unit and C-21 carbon atom of the macrolide core (Chart 1) in analogy with the telithromycin structure. As shown in Table 1 two methylene-unit linkers (11f, 11g, and 11h) greatly enhance the in vitro antibacterial activity compared with four methylene-unit linkers found in 11l, 11m, and 11n, respectively. For example, compounds 11f–h and 11l–n share the same quinoline heterocycle and identical substitution pattern, but compounds 11f–h have significantly improved potency against efflux- and constitutively MLSB-resistant S. pneumoniae and S. pyogenes strains as well as H. influezae strain.

Introduction of the double bond in the linker additionally improves the activity against constitutively MLSB-resistant S. pyogenes and H. influenzae especially in the case of methoxy substituted quinoline analogues (11j vs 11m and 11k vs 11n). In the case of unsubstituted quinoline analogues (11i vs 11l), the effect is not as profound but it slightly improves (4-fold) activity against efflux-resistant S. pneumoniae and S. pyogenes.

To further investigate the SAR we synthesized two representative ketolides in which a quinoxaline ring was appended to the macrolide core. It was found that the activity of the quinoxaline analogue 11o was in general 2- to 4-fold better in comparison to its glycyl-extended analogue 11p against most of the strains tested. In addition, comparison of compound 11o with telithromycin indicates that the former is more active against constitutively MLSB-resistant S. pyogenes and H. influenzae.

In summary, a series of clarithromycin γ-lactone ketolides were synthesized and evaluated as a novel class of macrolide antibiotics. By introducing heteroaromatic side-chain instead of α-amino group at the C-21 position of γ-lactone, the antibacterial activity against efflux- and MLSB-resistant strains of S. pneumoniae and S. pyogenes could be substantially enhanced. In particular heteroaromatic derivative 11o exhibited significantly potent antibacterial activity against not only erythromycin-susceptible Gram-positive pathogens but also inducibly MLSB-resistant S. aureus, efflux-resistant S. pneumoniae, and MLSB-constitutively resistant S. pneumoniae and S. pyogenes. Moreover, compound 11o is ca. 4-fold more active than telithromycin (1) against constitutively MLSB-resistant S. pyogenes and H. influenzae strain. It has been demonstrated that γ-lactone ketolides are innovative semisynthetic macrolides that have potential as a next-generation macrolide antibiotic.

Acknowledgments

The authors thank GSK microbiology group for the in vitro antibacterial screening of the products. D.P. would also like to thank S. Milković for excellent technical assistance and colleagues from PLIVA Research Institute for their help.

Glossary

Abbreviations

MLSB

macrolide-lincosamide-streptogramin B

HBTU

O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

DIPEA

diisopropylethylamine

SAR

structure–activity relationships

Supporting Information Available

General experimental methods, experimental procedures, and spectral data for selected new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

Author Present Address

§ (D.P.) St. Anne’s University Hospital, Pekarska 53, 656 91 Brno, Czech Republic. Phone: +420 549 49 5698.

The authors declare no competing financial interest.

Supplementary Material

ml500279k_si_001.pdf (2.3MB, pdf)

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Supplementary Materials

ml500279k_si_001.pdf (2.3MB, pdf)

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