cas 118058-74-5, 3-O-Decladinosyl-6-O-Methylerythronolide A

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A novel series of 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing 1,2,3-triazole group: Design, synthesis and antibacterial evaluation
A series of novel 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing the 1,2,3-triazole group were designed, synthesized, and evaluated for their in vitro antibacterial activity. The antibacterial results indicated that most of the target compounds not only increased their activity against resistant bacterial strains, but also partially retained the activity against sensitive bacterial strains compared with clarithromycin. Among them, 13d had the best antibacterial activity against resistant strains, including Streptococcus pneumoniae B1 expressing the ermB gene (16 μg/mL), Streptococcus pneumoniae AB11 expressing the mefA and ermB genes (16 μg/mL) and Streptococcus pyogenes R1 (16 μg/mL), showing >16, 8 and 16-fold higher activity than that of CAM, respectively. Moreover, 13d and 13g exhibited the best antibacterial activity against sensitive bacterial strains, including Staphylococcus aureus ATCC25923 (4 μg/mL) and Bacillus Subtilis ATCC9372 (1 μg/mL). The MBC results showed that the most promising compounds 13d and 13g exhibited antibacterial activity through bacteriostatic mechanism, while the time-kill kinetic experiment revealed bactericidal kinetics of 13g from microscopic point of view. In vitro antibacterial experiments and molecular docking results further confirmed that it was feasible to our initial design strategy by modifying the C-3 and C-11 positions of clarithromycin to increase the activity against resistant bacteria.
Teng, Yuetai,Qin, Yinhui,Song, Di,Liu, Xingbang,Ma, Yingang,Zhang, Panpan,Ma, Shutao
(2020)
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Synthesis of novel macrolide derivatives with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains and their antibacterial activity
In an effort to find new antibiotics, a novel series of 14-membered macrolides with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains has been synthesized based on commercially available clarithromycin. Chemical transformation of hydroxy group at position C-3 afforded range of ketolides and acylides. Compared to telithromycin, compound 15a demonstrated improved in vitro activity against erythromycin-susceptible and -resistant strains.
Xu, Peng,Liu, Lu,Chen, Xiao-zhuo,Li, Yun,Liu, Jian,Jin, Zhi-ping,Wang, Guang-qiang,Lei, Ping-sheng
p. 4079 - 4083
(2009)
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Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides
A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5?μg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125–1?μg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.
Jia, Li,Yan, Mi,Shen, Yan,Qin, Yinhui,Qiang, Shengsheng,Ma, Shutao
p. 3693 - 3697
(2017)
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Preparation of cyclic 2′,3′-carbamate derivatives of erythromycin macrolide antibiotics
Tricarbonylation of clarithromycin has been effected in a one-pot reaction with phosgene. The 11,12-diol moiety was closed into a cyclic carbonate, while the dimethylamino alcohol of the desosamine sugar was cyclised with loss of a methyl group to form a cyclic 2′,3′-carbamate. The 4″ hydroxyl group in clarithromycin was converted into a chloroformate group and subsequently to an allyl carbonate which on Pd-catalysis furnished a novel N-demethylclarithromycin 2′,3′-carbamate-11,12-carbonate. Hydrolytic removal of the cladinose sugar and a subsequent oxidation furnished the corresponding ketolide. The 11,12-cyclic carbonate moiety was cleaved by sodium azide to the 10,11-anhydro-9-ketone. 11-N-Arylated cyclic 11,12:2′,3′-dicarbamate derivatives were prepared in a copper(I) chloride aided reaction between aryl isocyanates and 10,11-anhydro 9-ketones. The products are novel N-arylated-N′-demethylated 11,12:2′,3′-dicarbamate ketolides derived from clarithromycin.
Heggelund, Audun,Undheim, Kjell
p. 3266 - 3277
(2007)
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Design, synthesis and antibacterial evaluation of novel C-11, C-9 or C-2′-substituted 3-O-descladinosyl-3-ketoclarithromycin derivatives
A novel series of 3-O-descladinosyl-3-keto-clarithromycin derivatives, including 11-O-carbamoyl-3-O-descladinosyl-3-keto-clarithromycin derivatives and 2′,9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives, were designed, synthesized and eval
Bai, Bingfang,Bi, Fangchao,Qin, Yinhui,Teng, Yuetai,Ma, Shutao
(2021)
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Macrolide-peptide conjugates as probes of the path of travel of the nascent peptides through the ribosome
Despite decades of research on the bacterial ribosome, the ribosomal exit tunnel is still poorly understood. Although it has been suggested that the exit tunnel is simply a convenient route of egress for the nascent chain, specific protein sequences serve to slow the rate of translation, suggesting some degree of interaction between the nascent peptide chain and the exit tunnel. To understand how the ribosome interacts with nascent peptide sequences, we synthesized and characterized a novel class of probe molecules. These peptide-macrolide (or "peptolide") conjugates were designed to present unique peptide sequences to the exit tunnel. Biochemical and X-ray structural analyses of the interactions between these probes and the ribosome reveal interesting insights about the exit tunnel. Using translation inhibition and RNA structure probing assays, we find the exit tunnel has a relaxed preference for the directionality (N → C or C → N orientation) of the nascent peptides. Moreover, the X-ray crystal structure of one peptolide derived from a positively charged, reverse Nuclear Localization Sequence peptide, bound to the 70S bacterial ribosome, reveals that the macrolide ring of the peptolide binds in the same position as other macrolides. However, the peptide tail folds over the macrolide ring, oriented toward the peptidyl transferase center and interacting in a novel manner with 23S rRNA residue C2442 and His69 of ribosomal protein L4. These data suggest that these peptolides are viable probes for interrogating nascent peptide-exit tunnel interaction.
Washington, Arren Z.,Benicewicz, Derek B.,Canzoneri, Joshua C.,Fagan, Crystal E.,Mwakwari, Sandra C.,Maehigashi, Tatsuya,Dunham, Christine M.,Oyelere, Adegboyega K.
p. 2621 - 2631
(2014)
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Synthesis and antibacterial activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2- enyl)-10, 11-anhydroclarithromycin derivatives
An allyl group was attached to 3-keto function of ketolides in the presence of allyl bromide and KOtBu. Consequently, the Heck reaction of the resulting 2, 3-dehydro-3-O-allyl-10, 11-anhydroclarithromycin derivatives, in the presence of palladium (II) acetate and tri(o-tolyl)phosphine, afforded a 3-O-(3-aryl-E-prop-2-enyl) sidechain, not the previously reported 3-O-(3-aryl-Z-prop-1-enyl) sidechain. The results suggested that some steric factors in Β-hydrogen elimination might regulate the isomerization. The activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives was low.
Liang, Jian-Hua,Dong, Li-Jing,Wang, Yue-Ying,Yao, Guo-Wei,An, Mao-Mao,Wang, Rui
p. 333 - 337
(2011)
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Synthesis and antibacterial activity of novel ketolides with 11,12-quinoylalkyl side chains
A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by coupling with building block 6 or 32. The corresponding targets 7a–n, 33b, and 33e were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides, compounds 33b and 33e, displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens.
Zhao, Zhe-hui,Zhang, Xiao-xi,Jin, Long-long,Yang, Shuang,Lei, Ping-sheng
p. 2358 - 2363
(2018/06/25)

Synthesis and antibacterial evaluation of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives
A series of novel 11-O-aralkylcarbamoyl-3-O-descladinosylclarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed potent activity against erythromycin-susceptible S. pyogenes, erythromycin-resistant S. pneumoniae A22072 expressing the mef gene and S. pneumoniae AB11 expressing the mef and erm genes. Besides, most of the target compounds exhibited moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372. In particular, compounds 11a, 11b, 11c, 11e, 11f and 11h were found to exert favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.015–0.125 μg/mL. Furthermore, compounds 10e, 11a, 11b and 11c showed superior activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.25–0.5 μg/mL. Additionally, compound 11c was the most effective against all the erythromycin-resistant S. pneumoniae strains (A22072, B1 and AB11), exhibiting 8-, 8- and 32-fold more potent activity than clarithromycin, respectively.
Jia, Li,Wang, Yinhu,Wang, Yanxia,Qin, Yinhui,Hu, Chaoyu,Sheng, Juzheng,Ma, Shutao
supporting information
p. 2471 - 2476
(2018/06/06)

Erythromycin A ketone antibiotic derivative and preparation method and application thereof
The invention discloses an erythromycin A ketone antibiotic derivative containing substituted quinoline or isoquinoline, a preparation method and application of the erythromycin A ketone antibiotic derivative, and a compound side-chain intermediate and a synthetic method. The key point is that the compound indicated in the formula I has efficacy of broad-spectrum antibiotics and antibacterial activity and anti-resistant bacterial activity which are capable of inhibiting gram-positive bacteria and gram-negative bacteria. The compound can serve as the broad-spectrum antibiotics, and meanwhile, antibacterial and antiviral activity of gram-positive bacteria and gram-negative bacteria are inhibited.
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Paragraph 0125; 0127; 0128

(2017/09/12)

Dicyclic clarithromycin derivative and purpose of dicyclic clarithromycin derivative as tumor cells proliferation inhibitor
The invention belongs to the technical field of medicine, and relates to a dicyclic clarithromycin derivative and a preparation method thereof and an application of the dicyclic clarithromycin derivative as a tumor cells proliferation inhibitor in prepara
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Paragraph 0124; 0125

(2017/05/20)

Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof
The invention discloses a series of erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, represented by a formula I. The invention also provides preparation methods and applications of the derivatives, and side-chain inte
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Paragraph 0277; 0278

(2016/10/08)

Theoretical and experimental investigation on clarithromycin, erythromycin A and azithromycin and descladinosyl derivatives of clarithromycin and azithromycin with 3-O substitution as anti-bacterial agents
Erythromycin A, clarithromycin and azithromycin are the three most important macrolide antibiotics and are all very widely used in the clinic. They act on the bacterial ribosome inhibiting protein synthesis. We have performed both NMR (transferred NOESY) and modelling studies in order to determine the conformations of these antibiotics when they are bound to ribosomes. All three drugs exhibit the folded-out conformation in the bound state, but the dominant conformation of azithromycin is not completely superimposable on the clarithromycin and erythromycin A 9-ketone structures. Modelling suggests that clarithromycin (based on a 14-membered ring) and its 3-O-substituted descladinosyl derivatives are conformationally rigid molecules; these are compounds which generally exhibit more activity against Gram-positive bacteria. Azithromycin (based on a 15-membered ring) and its 3-O-descladinosyl derivatives are flexible in silico and show more activity against Gram-negative bacteria in culture.
Arsic, Biljana,Awan, Abida,Brennan, Richard J.,Aguilar, Juan A.,Ledder, Ruth,McBain, Andrew J.,Regan, Andrew C.,Barber, Jill
supporting information
p. 1347 - 1354
(2014/11/08)

Synthesis and antibacterial activity of a novel series of acylides active against community acquired respiratory pathogens
A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by
Kumar, Rajesh,Rathy, Sujata,Hajare, Atul K.,Surase, Yogesh B.,Dullu, Jyoti,Jadhav, Jitendra S.,Venkataramanan,Chakrabarti, Anjan,Pandya, Manisha,Bhateja, Pragya,Ramkumar,Das, Biswajit
scheme or table
p. 476 - 481
(2012/03/11)

PROCESS FOR PREPARATION OF KETOLIDE INTERMEDIATES
The inventions discloses a process for preparation of compounds of Formula (IX), Wherein, R is C1 -C6 alkyl, R1 is hydrogen or a hydroxyl protecting group, and R2 is hydrogen or fluorine.
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Page/Page column 16

(2012/09/21)

Synthesis and antibacterial activity of novel 3-O-carbamoyl derivatives of clarithromycin and 11,12-cyclic carbonate azithromycin
Two series of novel 3-O-carbamoyl derivatives of clarithromycin and 11,12-cyclic carbonate azithromycin were designed, synthesized and evaluated for their in vitro antibacterial activities. Compounds 4j and 4k were the most potent activity against erythro
Zhang, Ling,Song, Linchen,Liu, Zhaopeng,Li, Hui,Lu, Yingdong,Li, Zerong,Ma, Shutao
experimental part
p. 915 - 922
(2010/04/29)

Macrolides
This invention relates to a novel class of antibiotic agents, more specifically to macrolides comprising an oxazolidinone structure, their preparation, pharmaceutical compositions containing them, their use and methods of treatment using them.
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Page/Page column 6; 16

(2010/03/02)

Ketolide Derivatives as Antibacterial Agents
Provided herein are ketolide derivatives, which can be used as antibacterial agents. Compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more parti
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Page/Page column 6; 10-11

(2009/01/24)

KETOLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS
The present invention provides ketolide derivatives, which can be used as anti-bacterial agents. Compounds disclosed herein can be used for the treating or preventing conditions caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more particularly against, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobactericeae or any combination thereof. Also provided are processes for preparing compounds disclosed herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods of treating bacterial infections.
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Page/Page column 25

(2009/07/17)

MACROLIDES DERIVATIVES AS ANTIBACTERIAL AGENTS
The present invention provides macrolide derivatives, which can be used as antibacterial agents. Compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram-positive, gram-negative or anaerobic bacteria
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Page/Page column 19

(2009/05/28)

Antibacterial Agents
The present invention provides acylide derivatives, which can be used as antibacterial agents. Compounds disclosed herein can be used for treating or preventing conditions caused by or contributed to by Gram-positive, Gram-negative or anaerobic bacteria, more particularly against, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobactericeae or any combination thereof. Also provided are processes for preparing compounds disclosed herein, pharmaceutical compositions thereof, and method of treating bacterial infections.
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Page/Page column 17; 10

(2009/01/24)

MACROLIDES DERIVATIVES AS ANTIBACTERIAL AGENTS
The present invention provides macrolide derivatives, which can be used as antibacterial agents. Compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram-positive, gram-negative or anaerobic bacteria
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Page/Page column 15; 35

(2010/11/27)

KETOLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS
The present invention provides ketolide derivatives, which can be used as antibacterial agents. In particular, compounds described herein can be used for treating or preventing conditions caused by or contributed to by Gram-positive, Gram-negative or anaerobic bacteria, more particularly against, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae. Also provided are processes for preparing siuch ketolide derivatives, pharmaceutical compositions thereof, and methods of treating bacterial infections.
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Page/Page column 48; 81

(2008/06/13)

ANTIBACTERIAL AGENTS
The present invention provides acylide derivatives, which can be used as antibacterial agents. Compounds disclosed herein can be used for the treatment or prevention of a condition caused by or contributed to by Gram-positive, Gram-negative or anaerobic b
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Page/Page column 11; 40

(2008/06/13)

KETOLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS
The present invention provides ketolide derivatives, which can be used as antibacterial agents. In particular, compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram positive, gram negative or anae
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Page/Page column 23

(2010/11/25)

Antibiotic agents
Methods of treating a microbial infection comprising administering to a patient in need of such treatment are disclosed. In one aspect the method comprises administering to a patient in need of such treatment a therapeutically effective amount of Erythromycin B (or a pharmaceutically acceptable derivative thereof). In another aspect the method comprises a pharmaceutical composition comprising at least 50% by weight of Erythromycin B (or a pharmaceutically acceptable derivative thereof) of the total weight of antibiotic present in the composition. Also disclosed are 2′-esters of Erythromycin B and Erythromycin B enol ether.
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Sheet 5

(2008/06/13)

Synthesis and antibacterial activity of a novel series of acylides: 3-O-(3-pyridyl)acetylerythromycin A derivatives
A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-stre
Tanikawa, Tetsuya,Asaka, Toshifumi,Kashimura, Masato,Suzuki, Keiko,Sugiyama, Hiroyuki,Sato, Masakazu,Kameo, Kazuya,Morimoto, Shigeo,Nishida, Atsushi
p. 2706 - 2715
(2007/10/03)

C-2 modified erythromycin derivatives
A compound having the formula selected from the group consisting of a compound of formula I a compound of formula II a compound of formula III as well as and pharmaceutically acceptable salts, esters, solvates, metabolites, and prodrugs thereof, are usefu
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Page column 51-53

(2010/02/05)

Synthesis and antibacterial activity of acylides (3-O-acyl-erythromycin derivatives): A novel class of macrolide antibiotics
Introduction of an acyl group to the 3-O-position of erythromycin A derivatives instead of L-cladinose led to a novel class of macrolide antibiotics that we named "acylides". The 3-O-nitrophenylacetyl derivative TEA0777 showed significantly potent activit
Tanikawa,Asaka,Kashimura,Misawa,Suzuki,Sato,Kameot,Morimoto,Nishida
p. 4027 - 4030
(2007/10/03)

Synthesis of 14,15-dehydroerythromycin A ketolides: Effects of the 13-substituent on erythromycin tautomerism
A ketolide was prepared from 14,15-dehydroerythromycin A by two different routes. The first approach involving oxidation of the 3-OH of 3-descladinosyl-14,15-dehydroerythromycin A 2′-O-acetate gave unexpectedly high levels of 3,11-double oxidation. This may be due to greater formation of the 9,12-hemiketal in 14,15-dehydroerythromycin A and concomitant exposure of the 11-OH group for oxidation. NMR studies of 14,15-dehydroerythromycin A support this hypothesis, revealing a 9:1 ratio of 9-ketone to 9,12-hemiketal in CDC13 and a 1:1 ratio in CD3OD as contrasted with the corresponding tautomer ratios of 30:1 in CDC13, and 6: 1 in CD3OD with erythromycin A. Alteration of the 13-substituent on the erythronolide A ring from ethyl to vinyl thus favors formation of the 9,12-hemiketal. A second route to the ketolides was developed based on these findings, in which the 11-OH is eliminated prior to oxidation of the 3-OH.
Fardis,Ashley,Carney,Chu
p. 278 - 284
(2007/10/03)

Acid-catalyzed degradation of clarithromycin and erythromycin B: A comparative study using NMR spectroscopy
One of the major drawbacks in the use of the antibiotic erythromycin A is its extreme acid sensitivity, leading to degradation in the stomach following oral administration. The modern derivative clarithromycin degrades by a different mechanism and much more slowly. We have studied the pathway and kinetics of the acid-catalyzed degradation of clarithromycin and of erythromycin B, a biosynthetic precursor of erythromycin A which also has good antibacterial activity, using 1H NMR spectroscopy. Both drugs degrade by loss of the cladinose sugar ring and with similar rates of reaction. These results suggest that erythromycin B has potential as an independent therapeutic entity, with superior acid stability compared with erythromycin A and with the advantage over clarithromycin of being a natural product.
Mordi, Mohd N.,Pelta, Michelle D.,Boote, Valerie,Morris, Gareth A.,Barber, Jill
p. 467 - 474
(2007/10/03)

Synthesis and antibacterial activity of ketolides (6-O-methyl-3- oxoerythromycin derivatives): A new class of antibacterials highly potent against macrolide-resistant and -susceptible respiratory pathogens
In the search for new antibiotics active against macrolide-resistant pneumococci and Haemophilus influenzae, we synthesized a new class of 3-oxo- 6-O-methylerythromycin derivatives, so-called 'ketolides'. A keto function was introduced in position 3 after removal of L-cladinose, a sugar which has long been thought essential. Further modifications of the macrolactone backbone allowed us to obtain three different series of 9-oxime, 11,12- carbamate, and 11,12-hydrazonocarbamate ketolides. These compounds were found to be very active against penicillin/erythromycin-resistant pneumococci and noninducers of MLS(B) resistance. The 11,-12-substituted ketolide 61 (HMR 3004) demonstrated a potent activity against multiresistant pneumococci associated with a well-balanced activity against all bacteria involved in respiratory infections including H. influenzae, Mycoplasma catarrhalis, group A streptococci, and atypical bacteria. In addition HMR 3004 displayed high therapeutic activity in animals infected by all major strains, irrespective of their resistance phenotype.
Agouridas, Constantin,Denis, Alexis,Auger, Jean-Michel,Benedetti, Yannick,Bonnefoy, Alain,Bretin, Fran?ois,Chantot, Jean-Fran?ois,Dussarat, Arlette,Fromentin, Claude,D'Ambrières, Solange Gouin,Lachaud, Sylvette,Laurin, Patrick,Martret, Odile Le,Loyau, Véronique,Tessot, Nicole
p. 4080 - 4100
(2007/10/03)