Structure-Activity Relationship Study of 6-O-Methylerythromycin 9-O-Substituted Oxime Derivatives.

Kawashima, Y.; Yamada, Yuki; Asaka, Toshifumi; Misawa, Yoko; Kashimura, Masato; Morimoto, Shigeo; Ono, Takeo; Nagate, Takatoshi; Hatayama, Katsuo; Hirono, Shuichi; Moriguchi, Ikuo

doi:10.1248/cpb.42.1088

Cited by 12 publications

(4 citation statements)

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“…Macrolides with 9-oxime substitutions have been studied previously (13,18). 9-Oxime-substituted analogs were more active than erythromycin against erythromycin-resistant organisms, such as the M. avium complex, Staphylococcus aureus (23), and Mycobacterium leprae (11).…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

Falzari

Zhu

Pan

et al. 2005

Antimicrob Agents Chemother

202

246

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Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of <4 M were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10-to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis.Tuberculosis (TB) has been recognized as a major public health problem worldwide, exacerbated greatly by the human immunodeficiency virus pandemic. The length and complexity of antibiotic therapy for tuberculosis and the emergence of multidrug-resistant strains make a compelling case for the development of new efficacious anti-TB drugs.The development of new members of classes of established antibiotics, such as the macrolides, which already possess many desirable pharmacological properties, is one approach to rapidly add new drugs to the existing anti-TB armamentarium.Although they are antibiotics of choice for several respiratory pathogens and have demonstrated efficacy in other mycobacterioses, such as leprosy (6,15,17) and Mycobacterium avium (14,26,27) infections, the macrolides developed to date have lacked potency against the tubercle bacillus (24). The clinical use of clarithromycin in treating tuberculosis is limited to multiple-drug-resistant cases in which there are few remaining treatment options (21).The current development goal for macrolides has been primarily to overcome ribosome modification and drug efflux, the major mechanisms of resistance to this antibiotic class (22). Methylation of A2058, located in the peptidyl transferase loop of domain V of the 23S rRNA subunit, by specific methylases (erm) decreases macrolide binding affinity, rendering the organisms resistant to macrolides, lincosamides, and streptogramins, known as the MLS B phenotype (28,29). Macrolides in which the cladinose group is replaced with a keto group (ketolides) avoid efflux-med...

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

Falzari

Zhu

Pan

et al. 2005

Antimicrob Agents Chemother

202

246

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“…Treatment of vancomycin (Van, 8 ) with propargylamine under HBTU coupling conditions yields fully active vancomycin alkyne ( 9 ) in good yield (Scheme ). The ketone functionality on erythromycin A (Eryc) has previously been modified as an oxime ether and shown not to reduce activity. , Treatment of commercially available erythromycin A oxime ( 10 ) with propargyl bromide yields erythromycin alkyne ( 11 ) in 30% yield (Scheme ). Recent studies have shown that loss of the piperazine ring on rifampicin (Rif) results in a substantial decrease in activity; therefore we chose to replace the 4-methylpiperazine group with a 4-propargylpiperazine unit.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Tridecaptin–Antibiotic Conjugates with in Vivo Activity against Gram-Negative Bacteria

Cochrane

et al. 2015

J. Med. Chem.

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A series of tridecaptin-antibiotic conjugates were synthesized and evaluated for in vitro and in vivo activity against Gram-negative bacteria. Covalently linking unacylated tridecaptin A1 (H-TriA1) to rifampicin, vancomycin, and erythromycin enhanced their activity in vitro but not by the same magnitude as coadministration of the peptide and these antibiotics. The antimicrobial activities of the conjugates were retained in vivo, with the H-TriA1-erythromycin conjugate proving a more effective treatment of Klebseilla pneumoniae infections in mice than erythromycin alone or in combination with H-TriA1.

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“…Therefore the presence of a keto function instead of a sugar in position 3 seemed to be critical with respect to the induction of resistance and to the activity against macrolide-resistant Gram-positive organisms. Recently, following the first report of ketolides by HMR, chemists from Taisho and Abbott have reported the synthesis of some interesting 9-imino tricyclic ketolides like TE 802, 25b, 2,3-unsaturated carbamates (so-called anhydrolides), 3-deoxycarbamates, and 3-acyl derivatives . However all these compounds are weakly active against constitutively resistant pneumococci and none of them are as effective as azithromycin or 61 against H. influenzae .…”

Section: Results and Discussion45mentioning

confidence: 99%

“…During the last 30 years several chemical modifications have been made on the macrolactone part of erythromycin and the two sugars, cladinose 14,24b and desosamine. ,28b For instance, the introduction of oximes 4,16 and amines 17 at C-9, C-15 azalide synthesis via the Beckmann rearrangement of 9-oxime, and 6,11,12- O -alkylation 5,19 or 8-fluorination 20 have culminated with the synthesis of new drugs such as roxithromycin, dirithromycin, azithromycin, clarithromycin, and flurithromycin. More recently, new chemical approaches have generated some interesting series such as 9-deoxo-12-deoxy-9,12-epoxyerythromycin A derivatives, C-14 azalides, C-21 aminomethylene, and finally 11,12-cyclocarbamates 24 and 9-azaimino-11,12-cyclocarbamates . Some products coming from mutants and genetically engineered Streptomyces have also been described .…”

Section: Introductionmentioning

confidence: 99%

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

Agouridas¹,

Denis²,

Auger³

et al. 1998

J. Med. Chem.

204

122

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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 MLSB 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.

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Structure-Activity Relationship Study of 6-O-Methylerythromycin 9-O-Substituted Oxime Derivatives.

Cited by 12 publications

References 0 publications

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

Synthesis of Tridecaptin–Antibiotic Conjugates with in Vivo Activity against Gram-Negative Bacteria

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

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