- Synthesis and antibacterial activity of novel 3-O-descladinosylazithromycin derivatives
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Novel series of novel 3-O-arylalkylcarbamoyl descladinosylazithromycin derivatives with the 2′-O-acetyl and 11,12-cyclic carbonate groups, the 11,12-cyclic carbonate group and the 11-O-arylalkylcarbamoyl side chain, and 2′-O-arylalkylcarbamoyl descladinos
- Yan, Mi,Ma, Ruixin,Jia, Li,Venter, Henrietta,Ma, Shutao
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- Design, synthesis and structure-activity relationships of novel 15-membered macrolides: Quinolone/quinoline-containing sidechains tethered to the C-6 position of azithromycin acylides
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In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.
- Aldrich, Courtney,Brody, Scott,Cushman, Mark,Fan, Bing-Zhi,Hiasa, Hiroshi,Liang, Jian-Hua,Lv, Wei,Yang, Zhao-Yong
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- Synthesis and antibacterial evaluation of a series of 11,12-cyclic carbonate azithromycin-3-O-descladinosyl-3-O-carbamoyl glycosyl derivatives
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A novel series of 11,12-cyclic carbonate azithromycin-3-O-descladinosyl-3-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against seven kinds of susceptible strains. In particular, compound G1 exhibited the most potent activity against methicillin-resistant Streptococcus pneumoniae 943 (MIC: 1 μg/mL), Staphylococcus pneumoniae 746 (MIC: 2 μg/mL), Streptococcus pyogenes 447 (MIC: 8 μg/mL), and Escherichia coli 236 (MIC: 32 μg/mL), which were two-, four-, four-, four-, and eight-fold stronger activity than azithromycin, respectively. Additionally, compound G2 exhibited improved activity against methicillin-resistant Staphylococcus aureus MRSA-1 (MIC: 8 μg/mL), Streptococcus pneumoniae 943 (MIC: 2 μg/mL), Staphylococcus pneumoniae 746 (MIC: 2 μg/mL), and Escherichia coli 236 (MIC: 32 μg/mL), which were two-, two-, four-, and eight-fold better activity than azithromycin, respectively. As for methicillin-resistant Staphylococcus aureus MRSA-1, compound G6 presented the most excellent activity (MIC: 4 μg/mL), showing four-fold higher activity than azithromycin (MIC: 16 μg/mL) and erythromycin (MIC: 16 μg/mL). However, compared with other compounds, compounds G7 and G8 with the disaccharide side chain were observed the lower activity against seven strains.
- Wang, Chao-Ming,Zhao, Feng-Lan,Zhang, Lei,Chai, Xiao-Yun,Meng, Qing-Guo
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- Novel hybrid molecules based on 15-membered azalide as potential antimalarial agents
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Malaria remains the most prevalent tropical disease, and due to the spread of resistant parasites novel therapeutics are urgently needed. Azithromycin has shown potential in malaria treatment so we designed hybrid azalide molecules with the aim to improve activity against and selectivity for the malaria parasite. Novel hybrid molecules comprising 4-aminoquinoline moiety covalently liked to 15-membered azalide scaffold at position C-3′ were synthesized and biologically evaluated. Antimalarial testing against Plasmodium falciparum sensitive and resistant strains confirmed the improved in vitro activity over azithromycin and chloroquine. Selectivity of the compounds (HepG2 IC 50/P. falciparum IC50 ratio) for the parasite was high (100-2700) and their antibacterial activity diminished. Even though oral bioavailability determined for compound 12 was low, novel quinoline C-3′-substituted 15-membered azalides represent an interesting subclass of antimalarial macrolides that need further research and evaluation.
- Star?evi?, Kristina,Pe?i?, Dijana,Toplak, Ana,Landek, Goran,Alihod?i?, Sulejman,Herreros, Esperanza,Ferrer, Santiago,Spaventi, Radan,Peri?, Mihaela
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- Synthesis and Antibacterial Activity of New N-Alkylammonium and Carbonate-Triazole Derivatives within Desosamine of 14- and 15-Membered Lactone Macrolides
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Desosamines of azithromycin (AZM) and clarithromycin (CLA) were modified by N-alkylation or nucleophilic substitution at the carbonyl/CuAAC sequence. Biological studies revealed a higher antibacterial potency of quaternary N-alkylammonium bromides of CLA as compared to AZM. SAR studies of CLA salts, including biological, conformation and molecular-docking analysis, enriched by physicochemical parameters, showed the importance of less bulky and unsaturated substituent for an efficient docking mode at the ribosomal tunnel and good antibacterial potency against clinical and standard Streptococcus pneumoniae and Streptococcus pyogenes strains (MICs 0.25 or 0.5 μg/mL). These CLA salts also have an at least threefold lower cytotoxicity than reference antibiotics at comparable antibacterial activity against the S. pneumoniae clinical strain. Differences in antibacterial effects noted for AZM and CLA salts bearing less bulky N-substituents can be better understood when their binding modes in the ribosomal tunnel are considered rather than their common low lipophilicity and excellent water solubility.
- Janas, Anna,Pecyna, Paulina,Gajecka, Marzena,Bartl, Franz,Przybylski, Piotr
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- 3 - O -aralkyl substituted RMB 15-azlactone derivative as well as preparation method and application thereof
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The invention relates to the field of medicines, in particular to 3-O - aralkyl substituted RMB 15-azlactone derivatives as well as a preparation method and application thereof. 3 - O -arylalkyl-substituted RMB 15-azlactone-based derivatives having the structure of general formula I. In-flight R1 An aryl group or a substituted aryl group. R2 From hydrogen. Acetyl or benzoyl. The 3-O - aralkyl substituted RMB 15-azlactone derivative shows significant antibacterial activity on various gram-positive bacteria and gram-negative bacteria, and especially has good antibacterial activity on clinically isolated enterococcus faecium strain, methicillin-resistant staphylococcus aureus and penicillin-resistant staphylococcus aureus.
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Paragraph 0108-0111
(2021/08/25)
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- Design, synthesis and antibacterial evaluation of novel 3-O-substituted 15-membered azalides possessing 1,2,3-triazole side chains
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The acquired and intrinsic resistance of bacteria to macrolide antibiotics limits the clinical application of these agents, and thus it is particularly important to discover novel macrolide antibiotics that can be administered to counteract the prevalence of bacterial resistance. In this study, we introduced some active 1,2,3-triazole side chains into the azithromycin at position 3-O, thereby obtaining a number of 3-O-substituted 15-membered azalides. Determination of the minimum inhibitory concentration (MIC) of these target compounds revealed that the compound 9g possessed the strongest antibacterial activity (MIC = 8–16 μg/mL) against drug-resistant strains and was generally 16- to 32-fold more active than the azithromycin (MIC ≥ 256 μg/mL). Combined analysis of the results of antibacterial activity together with theoretically calculated lipid/water partition coefficients (ClogP) indicated the importance of the chemical nature of the alkyl groups attached to the 1,2,3-triazole side chain in conferring promising antibacterial activity. The findings of molecular docking analyses indicated that compound 9g may bind to the A752 base of 23S rRNA in bacterial ribosome via hydrophobic or electrostatic interactions, resulting in the excellent antibacterial activity of this compound. Furthermore, the data of minimum bactericidal concentration revealed that compounds 9e, 9f, 9g and 9h are excellent bacteriostatic agents. In addition, the study of bactericidal kinetics confirmed that compound 9g is a time- and concentration-dependent agent.
- Qin, Yinhui,Xu, Linlin,Teng, Yuetai,Yang, Yan,Wang, Yinhu,Ma, Peizhi
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supporting information
(2021/08/23)
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- Macrolide derivative and application thereof
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The invention provides a macrolide derivative of a novel structure. Experiments show that the macrolide derivative has a good promoting effect on alimentary motility and is capable of enhancing intestine peristalsis, increasing defecation quantity and accelerating passing of intestinal content; on such basis, it is further discovered that the macrolide derivative is low in antibiotic activity and small in side effect and can be taken as a gastrointestinal motility promoting drug. Particularly, a compound III-3 screened with the optimal efficacy is subjected to further efficacy evaluation as well as acute toxicity and cardiotoxicity evaluation by domestic rabbits, beagles and marmosets. Experiments show that the compound III-3 is safe and capable of effectively promoting gastrointestinal motility, thereby being excellent in druggability.
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Paragraph 0022; 0048
(2017/08/28)
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- AZITHROMYCIN DERIVATIVES WITH EPITHELIAL BARRIER ENHANCEMENT PROPERTIES
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The invention provides novel compounds that are derivatives of Azithromycin and that have been found by the current inventors to have low antimicrobial activity but significant epithelial barrier enhancement properties. The invention further provides use of the compounds as a medicament, in particular in the treatment or prophylaxis of a disease or condition that is caused by a defect in epithelial cells or tissue, or a disease or condition that benefits from enhancement or restoration of epithelial barrier function, for example diseases of the respiratory tract.
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Page/Page column 35; 36
(2017/06/12)
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- 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
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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
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supporting information
p. 1347 - 1354
(2014/11/08)
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- Synthesis and antibacterial activity of novel 3-O-carbamoyl derivatives of clarithromycin and 11,12-cyclic carbonate azithromycin
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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
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experimental part
p. 915 - 922
(2010/04/29)
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- 3'-N-SUBSTITUTED 9-DEOXO-9A-METHYL-9A-AZA-HOMOERYTHROMYCIN HAVING ANTIMALARIAL ACTIVITY
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The present invention relates to novel 3'-N-substituted 9-deoxo-9a-methyl-9a-aza-9a- homoerythromycin A derivatives having antimalarial activity. More particularly, the invention relates to 3'-N-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A and 3'-N-substituted-3-O-decladinosyl-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives having antimalarial activity, to the intermediates for their preparation, to the methods for their preparation, to their use as therapeutic agents, and to salts thereof having antimalarial activity.
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Page/Page column 34
(2010/08/09)
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- MACROLIDE DERIVATIVES
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Compounds represented by formula (I) and the formula (IV) have an inhibitory activity of MMP-9 production, therefore, are useful as a medicine agent with fewer side effects than conventional MMP enzyme activity inhibitors, as a prophylactic and therapeuti
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Page/Page column 26
(2009/04/24)
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- Antibiotic agents
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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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