RESUMEN
We present a new efficient green synthetic protocol for introduction of substituents to the C-6 position of 2-arylbenzothiazole nuclei. Newly synthesized compounds were designed to study the influence of the hydroxy and methoxy groups on the 2-arylbenzothiazole scaffold, as well as the influence of the type of substituents placed on the C-6 position of benzothiazole moiety on biological activity, including antibacterial, antitumor and antioxidant activity. Modest activity was observed against the tested Gram-positive and Gram-negative bacterial strains for only amidino derivatives 5d and 6d. The tested compounds exhibited moderate to strong antiproliferative activity towards the tumor cell lines tested. The SAR study revealed that the introduction of substituents into the benzene ring of the benzothiazole nuclei is essential for antiproliferative activity, while introduction of the hydroxy group into the 2-aryl moiety of the 2-arybenzothiazole scaffold significantly improved selectivity against tumor cell lines. The observed results revealed several novel 6-substituted-2-arylbenzothiazole compounds, 5b, 5c, 5f and 6f, with strong and selective antiproliferative activity towards HeLa cells in micro and submicromolar concentrations, with the most selective compounds being 6-ammonium-2-(2-hydroxy/methoxyphenyl)benzothiazoles 5f and 6f. The compound 5f bearing the hydroxy group on the 2-arylbenzothiazole core showed the most promising antioxidative activity evaluated by DPPH, ABTS and FRAP in vitro assays. The presence of the amino protonated group attached at the benzothiazole moiety was essential for the antiproliferative and antioxidant activity observed, exerted through a change in the levels of the reactive oxygen species-modulated HIF-1 protein.
Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , Tecnología Química Verde , Benzotiazoles/síntesis química , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión/métodos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Análisis Espectral/métodos , Relación Estructura-ActividadRESUMEN
The human microbiota is a diverse microbial ecosystem associated with many beneficial physiological functions as well as numerous disease etiologies. Dominated by bacteria, the microbiota also includes commensal populations of fungi, viruses, archaea, and protists. Unlike bacterial microbiota, which was extensively studied in the past two decades, these non-bacterial microorganisms, their functional roles, and their interaction with one another or with host immune system have not been as widely explored. This review covers the recent findings on the non-bacterial communities of the human gastrointestinal microbiota and their involvement in health and disease, with particular focus on the pathophysiology of inflammatory bowel disease.
Asunto(s)
Archaea , Bacterias , Microbioma Gastrointestinal , Micobioma , Parásitos , Viroma , Animales , Susceptibilidad a Enfermedades , Disbiosis , Eucariontes , Humanos , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , SimbiosisRESUMEN
Novel nitro (3a-3f)- and amino (4a-4f and 5a-5f)-substituted 2-benzimidazolyl and 2-benzothiazolyl benzo[b]thieno-2-carboxamides were designed and synthesized as potential antibacterial agents. The antibacterial activity of these compounds has been evaluated against Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Moraxella catarrhalis). The most promising antibacterial activity was observed for the nitro- and amino-substituted benzimidazole derivatives 3a, 4a, 5a and 5b with MICs 2-8 [Formula: see text]. Additionally, compounds with inferior antibacterial activity were further tested for their antiproliferative activity in vitro against three human cancer cell lines. Amino-substituted benzothiazole hydrochloride salt 5d displayed the most pronounced and selective activity against the MCF-7 cell line with an [Formula: see text] of 40 nM. Furthermore, DNA binding experiments of selected derivatives indicated that DNA cannot be considered as a primary biological target for this type of compounds.
Asunto(s)
Antibacterianos , Antineoplásicos , Bencimidazoles , Benzotiazoles , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/metabolismo , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/crecimiento & desarrollo , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Humanos , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/crecimiento & desarrollo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
Liver fibrosis is a progressive pathological process resulting in an accumulation of excess extracellular matrix proteins. We discovered that bone morphogenetic protein 1-3 (BMP1-3), an isoform of the metalloproteinase Bmp1 gene, circulates in the plasma of healthy volunteers and its neutralization decreases the progression of chronic kidney disease in 5/6 nephrectomized rats. Here, we investigated the potential role of BMP1-3 in a chronic liver disease. Rats with carbon tetrachloride (CCl4)-induced liver fibrosis were treated with monoclonal anti-BMP1-3 antibodies. Treatment with anti-BMP1-3 antibodies dose-dependently lowered the amount of collagen type I, downregulated the expression of Tgfb1, Itgb6, Col1a1, and Acta2 and upregulated the expression of Ctgf, Itgb1, and Dcn. Mehanistically, BMP1-3 inhibition decreased the plasma levels of transforming growth factor beta 1(TGFß1) by prevention of its activation and lowered the prodecorin production further suppressing the TGFß1 profibrotic effect. Our results suggest that BMP1-3 inhibitors have significant potential for decreasing the progression of fibrosis in liver cirrhosis.
Asunto(s)
Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Cirrosis Hepática/tratamiento farmacológico , Actinas/genética , Actinas/metabolismo , Animales , Anticuerpos/inmunología , Anticuerpos/uso terapéutico , Proteínas Morfogenéticas Óseas/inmunología , Tetracloruro de Carbono/toxicidad , Línea Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Decorina/genética , Decorina/metabolismo , Humanos , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
A set of novel quinolone-triazole conjugates (12-31) were synthesized in three steps in good yields starting from 2-phenylquinoline-4-carboxylic acid. All the intermediates, as well as the final 1,2,4-triazolyl quinolines were fully characterized by their detailed spectral analysis utilizing different techniques such as IR, 1H NMR, 13C NMR, and finally mass spectrometry. All the synthesized compounds were evaluated in vitro for their potential antibacterial activity and their preliminary safety profile was assessed through cytotoxicity assay. Additionally, six selected conjugates were evaluated for their antioxidative properties on the basis of density functional theory calculations, using radical scavenging assay (DPPH) and cellular antioxidant assay. The reported results encourage further investigation of selected compounds and are shading light on their potential pharmacological use.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antioxidantes/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Triazoles/farmacología , Antibacterianos/síntesis química , Antioxidantes/síntesis química , Antioxidantes/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Teoría Cuántica , Quinolinas/síntesis química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
Versatile 1,2,3-triazole pharmacophore-based benzofused heterocycles containing halogen-substituted aromatic (9-17 and 25-28), 7-substituted coumarin (18-23 and 29-30) or penciclovir-like subunit (31a,b-38a) were designed and synthesized to evaluate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. Hybridization approach using environmentally friendly Cu(I)-catalyzed click reaction under microwave irradiation was adopted in the synthesis of regioselective 1,4-disubstituted 1,2,3-triazole tethered heterocycles (9-23 and 25-30), while post-N-alkylation of NH-1,2,3-triazoles afforded both 2,4- (31a-38a) and 1,4-disubstituted (31b-33b, 35b-37b) 1,2,3-triazole regioisomers. The compounds 18-23 and 25-30 revealed fluorescence in the violet region of the visible spectrum with a strong influence of phenyl spacer in 25-30 on both wavelength and emission intensity. Fusion of selected subunits led to new hybrid architecture, benzothiazole-1,2,3-triazole-coumarin 29 that demonstrated extremely narrow spectrum activity towards fastidious Gram-negative bacteria Moraxella catarrhalis. Selected hybrid showed the potency against Moraxella catarrhalis (MIC⩽0.25µg/mL) comparable to that of reference antibiotic azithromycin, which suggested that further investigations are necessary to optimize this potential hit compound as a new anti-Moraxella catarrhalis agent.
Asunto(s)
Antibacterianos/farmacología , Benzotiazoles/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Moraxella catarrhalis/efectos de los fármacos , Triazoles/farmacología , Umbeliferonas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Azitromicina/farmacología , Benzotiazoles/síntesis química , Química Clic , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Interacciones Hidrofóbicas e Hidrofílicas , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Umbeliferonas/síntesis químicaRESUMEN
A well-known class of antibacterials, 14- and 15-membered macrolides are widely prescribed to treat upper and lower respiratory tract infections. Azithromycin is a 15-membered macrolide antibiotic possessing a broad spectrum of antibacterial potency and favorable pharmacokinetics. Bacterial resistance to marketed antibiotics is growing rapidly and represents one of the major global hazards to human health. Today, there is a high need for discovery of new anti-infective agents to combat resistance. Recently discovered conjugates of azithromycin and thiosemicarbazones, the macrozones, represent one such class that exhibits promising activities against resistant pathogens. In this paper, we employed an approach which combined LC-SPE/cryo NMR, MS/MS and molecular modeling for rapid separation, identification and characterization of bioactive macrozones and their diastereomers. Multitrapping of the chromatographic peaks on SPE cartridges enabled sufficient sample quantities for structure elucidation and biological testing. Furthermore, two-dimensional NOESY NMR data and molecular dynamics simulations revealed stereogenic centers with inversion of chirality. Differences in biological activities among diastereomers were detected. These results should be considered in the process of designing new macrolide compounds with bioactivity. We have shown that this methodology can be used for a fast screening and identification of the macrolide reaction components, including stereoisomers, which can serve as a source of new antibacterials.
RESUMEN
A series of tetrahydropyrimidinyl-substituted benzimidazoles attached to various aliphatic or aromatic residues via phenoxymethylene were synthesised to investigate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. The influence of the type of substituent at the C-3 and C-4 positions of the phenoxymethylene linker on the antibacterial activity was observed, showing that the aromatic moiety improved the antibacterial potency. Of all the evaluated compounds, benzoyl-substituted benzimidazole derivative 15a was the most active compound, particularly against the Gram-negative pathogens E. coli (MIC = 1 µg mL-1) and M. catarrhalis (MIC = 2 µg mL-1). Compound 15a also exhibited the most promising antibacterial activity against sensitive and resistant strains of S. pyogenes (MIC = 2 µg mL-1). Significant stabilization effects and positive induced CD bands strongly support the binding of the most biologically active benzimidazoles inside the minor grooves of AT-rich DNA, in line with docking studies. The predicted physico-chemical and ADME properties lie within drug-like space except for low membrane permeability, which needs further optimization. Our findings encourage further development of novel structurally related 5(6)-tetrahydropyrimidinyl substituted benzimidazoles in order to optimize their antibacterial effect against common respiratory pathogens.
RESUMEN
A set of novel macrolones containing the flexible C8 basic linker and quinolone 3-(2'-hydroxyethyl)carboxamido group has been prepared and structurally characterized by NMR and IR spectroscopy, mass spectrometry and molecular modeling. The new compounds were evaluated in vitro against a panel of erythromycin-susceptible and erythromycin-resistant Gram-positive and Gram-negative bacterial strains. Compared to azithromycin, most of the compounds exhibited improved in vitro potency against the key respiratory pathogens.
Asunto(s)
Antibacterianos/síntesis química , Azitromicina/análogos & derivados , Macrólidos/síntesis química , Quinolonas/síntesis química , Antibacterianos/química , Azitromicina/síntesis química , Humanos , Macrólidos/química , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Quinolonas/química , Relación Estructura-ActividadRESUMEN
Cystic fibrosis is associated with chronic Pseudomonas aeruginosa colonization and inflammation. The role of MyD88, the shared adapter protein of the proinflammatory TLR and IL-1R families, in chronic P. aeruginosa biofilm lung infection is unknown. We report that chronic lung infection with the clinical P. aeruginosa RP73 strain is associated with uncontrolled lung infection in complete MyD88-deficient mice with epithelial damage, inflammation, and rapid death. Then, we investigated whether alveolar or myeloid cells contribute to heightened sensitivity to infection. Using cell-specific, MyD88-deficient mice, we uncover that the MyD88 pathway in myeloid or alveolar epithelial cells is dispensable, suggesting that other cell types may control the high sensitivity of MyD88-deficient mice. By contrast, IL-1R1-deficient mice control chronic P. aeruginosa RP73 infection and IL-1ß Ab blockade did not reduce host resistance. Therefore, the IL-1R1/MyD88 pathway is not involved, but other IL-1R or TLR family members need to be investigated. Our data strongly suggest that IL-1 targeted neutralizing therapies used to treat inflammatory diseases in patients unlikely reduce host resistance to chronic P. aeruginosa infection.
Asunto(s)
Interleucina-1beta/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Receptores Tipo I de Interleucina-1/inmunología , Animales , Humanos , Inmunidad Innata , Interleucina-1beta/genética , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Infecciones por Pseudomonas/metabolismo , Receptores Tipo I de Interleucina-1/genética , Transducción de Señal , Receptores Toll-Like/inmunologíaRESUMEN
Fifteen-membered 8a-aza-8a-homoerythromycins derived from either erythromycin or clarithromycin have been acylated to form 4''-O-propenoyl derivative. These functionalized analogues underwent Michael reaction with primary or secondary amines to afford novel 8a-aza-8a-homoerythromycin-4''-(3-substituted-amino)propionates. This preparative sequence was adapted so that analogues could be made by parallel synthesis. Among them, 4-quinolone derivatives show particularly good antibacterial potency against macrolide resistant bacteria, comparable or better than azithromycin and telithromycin.
Asunto(s)
Antibacterianos/farmacología , Eritromicina/análogos & derivados , Antibacterianos/química , Bacterias/clasificación , Bacterias/efectos de los fármacos , Eritromicina/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
The synthesis and antimicrobial activity of a new class of macrolide antibiotics which consist of a macrolide scaffold and a quinolone unit covalently connected by an appropriate linker are described. Optimization of several synthetic steps and structural properties of lead compound 26 are discussed. Promising antibacterial properties of this compound and some of its analogues are reported.
Asunto(s)
Antibacterianos/síntesis química , Macrólidos/síntesis química , Macrólidos/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Microbiana , Humanos , Macrólidos/química , Conformación Molecular , Estructura Molecular , Quinolonas/química , Relación Estructura-ActividadRESUMEN
In this paper synthesis of macrolones 1-18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C-C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4''-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C-C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.
Asunto(s)
Azitromicina/análogos & derivados , Reactivos de Enlaces Cruzados/química , Éteres/química , Macrólidos/química , Reactivos de Enlaces Cruzados/síntesis química , Éteres/síntesis química , Humanos , Macrólidos/síntesis química , Modelos Químicos , Estructura MolecularRESUMEN
Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antimaláricos/farmacología , Descubrimiento de Drogas , Macrólidos/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antimaláricos/síntesis química , Antimaláricos/química , Bacterias/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Macrólidos/síntesis química , Macrólidos/química , Malaria/tratamiento farmacológicoRESUMEN
We introduce a three-dimensional stochastic reaction-diffusion model to describe MinD/MinE dynamical structures in Escherichia coli. This model spontaneously generates pole-to-pole oscillations of the membrane-associated MinD proteins, MinE ring, as well as filaments of the membrane-associated MinD proteins. Experimental data suggest MinD filaments are two-stranded. In order to model them we assume that each membrane-associated MinD protein can form up to three bonds with adjacent membrane-associated MinD molecules and that MinE induced hydrolysis strongly depends on the number of bonds MinD has established.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Relojes Biológicos/fisiología , Proteínas de Ciclo Celular/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Proteínas de la Membrana/metabolismo , Modelos Biológicos , Adenosina Trifosfatasas/química , Proteínas de Ciclo Celular/química , Simulación por Computador , Difusión , Dimerización , Escherichia coli/química , Proteínas de Escherichia coli/química , Proteínas de la Membrana/química , Modelos Químicos , Modelos Moleculares , Modelos Estadísticos , Procesos EstocásticosRESUMEN
Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.
Asunto(s)
Antibacterianos/síntesis química , Azitromicina/síntesis química , Macrólidos/síntesis química , Microsomas Hepáticos/efectos de los fármacos , Infecciones Neumocócicas/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacos , Administración Oral , Animales , Antibacterianos/farmacocinética , Azitromicina/análogos & derivados , Azitromicina/farmacocinética , Disponibilidad Biológica , Ácidos Carboxílicos/química , Cristalografía por Rayos X , Estabilidad de Medicamentos , Ésteres/química , Humanos , Inyecciones Intravenosas , Macrólidos/farmacocinética , Masculino , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Infecciones Neumocócicas/microbiología , Ratas , Ratas Wistar , Streptococcus pneumoniae/crecimiento & desarrolloRESUMEN
The new ureas and thioureas of 15-membered azalides, N''-substituted 9a-(N'-carbamoyl-gamma-aminopropyl) (4), 9a-(N'-thiocarbamoyl-gamma-aminopropyl) (6), 9a-[N'-(beta-cyanoethyl)-N'-(carbamoyl-gamma-aminopropyl)] (8) and 9a-[N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-gamma-aminopropyl)] (10) of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2), were synthesized and structurally characterized by NMR and IR spectroscopic methods and mass spectrometry. The new compounds were evaluated in vitro against a panel of erythromycin susceptible and erythromycin-resistant gram-positive and gram-negative bacterial strains. These compounds displayed an excellent overall antibacterial in vitro activity against erythromycin sensitive gram-positive strains, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and good against negative strains, Moraxella catarrhalis and Haemophilus influenzae. In addition, several ureas with naphthyl substituents (4f, 4g, 4h) showed better activity in comparison to azithromycin against inducible resistant S. pyogenes. Ureas with naphthyl substituents 4g, 4h and thiourea 8h displayed moderate activity against constitutively resistant S. pneumoniae.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Eritromicina/análogos & derivados , Tiourea/farmacología , Urea/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Estabilidad de Medicamentos , Eritromicina/síntesis química , Eritromicina/química , Eritromicina/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/química , Urea/síntesis química , Urea/químicaRESUMEN
A series of 4''-O-acyl derivatives of 8a-aza-8a-homoerythromycins A were synthesized and tested against Gram-positive and Gram-negative bacteria. Derivatives of 8a-aza-8a-homoerythromycin A have potent anti-bacterial activity against not only azithromycin-susceptible strains, but also efflux (M) and inducible macrolide-lincosamide-streptogramin-resistant Gram-positive pathogens. These compounds show moderate to high clearance and low oral bioavailability in preliminary in vivo pharmacokinetic studies in rat.