Comparative Evaluation of the Antibacterial and Antitumor Activities of 9-Phenylfascaplysin and Its Analogs.

Based on the results of our own preliminary studies, the derivative of the marine alkaloid fascaplysin containing a phenyl substituent at C-9 was selected to evaluate the therapeutic potential in vivo and in vitro. It was shown that this compound has outstandingly high antimicrobial activity against Gram-positive bacteria, including antibiotic-resistant strains in vitro. The presence of a substituent at C-9 of the framework is of fundamental importance, since its replacement to neighboring positions leads to a sharp decrease in the selectivity of the antibacterial action, which indicates the presence of a specific therapeutic target in bacterial cells.

Antibacterial Conjugates of Kanamycin A with Vancomycin and Eremomycin: Biological Activity and a New MS-Fragmentation Pattern of Cbz-Protected Amines.

A significant increase of microbial resistance to glycopeptides (especially vancomycin-resistant enterococci and ) prompted researchers to design new semisynthetic glycopeptide derivatives, such as dual-action antibiotics that contain a glycopeptide molecule and an antibacterial agent of a different class. We synthesized novel dimeric conjugates of kanamycin A with glycopeptide antibiotics, vancomycin and eremomycin. Using tandem mass spectrometry fragmentation, UV, IR, and NMR spectral data, it was unequivocally proven that the glycopeptide is attached to the kanamycin A molecule at the position 1 of 2-deoxy-D-streptamine.

Semisynthetic Amides of Polyene Antibiotic Natamycin.

Natamycin is a macrolide polyene antibiotic, characterized by a potent broad spectrum antifungal activity and low toxicity. However, it is not used for the treatment of systemic mycoses due to its low bioavailability and low solubility in aqueous solutions. In order to create new semisynthetic antifungal agents for treatment of mycoses, a series of water-soluble amides of natamycin were synthesized.

Evaluation of New Antimicrobial Agents Based on (1-Indol-3-yl)methylium Salts: Activity, Toxicity, Suppression of Experimental Sepsis in Mice.

The antimicrobial activity and toxicity of three novel synthetic antibacterial agents containing (1-indol-3-yl)methylium fragment were studied in vitro and in vivo. All compounds in vitro revealed high activity (minimal inhibitory concentration (MIC) 0.13-1.

Gausemycins A,B: Cyclic Lipoglycopeptides from Streptomyces sp.*.

We report a novel family of natural lipoglycopeptides produced by Streptomyces sp. INA-Ac-5812. Two major components of the mixture, named gausemycins A and B, were isolated, and their structures were elucidated.

Aminoalkylamides of Eremomycin Exhibit an Improved Antibacterial Activity.

After decades, the glycopeptide vancomycin is still the preferred antibiotic against resistant strains of Gram-positive bacteria. Although its clinical use is strictly regulated, the gradual spread of vancomycin-resistant bacteria, such as glycopeptide-resistant and glycopeptide-intermediate and vancomycin-resistant spp., is a serious health problem.

-(Hydroxyalkyl) Derivatives of (1-indol-3-yl)methylium Salts as Promising Antibacterial Agents: Synthesis and Biological Evaluation.

The wide spread of pathogens resistance requires the development of new antimicrobial agents capable of overcoming drug resistance. The main objective of the study is to elucidate the effect of substitutions in (1-indol-3-yl)methylium derivatives on their antibacterial activity and toxicity to human cells. A series of new compounds were synthesized and tested.

Synthesis and antibacterial activity of novel arylbis(indol-3-yl)methane derivatives.

A series of new compounds-arylbis(indol-3-yl)methylium derivatives-were synthesized and their antimicrobial activity was evaluated. All the compounds turned out to be highly active, with MIC depending on their structure and the length of N-alkyl residues. The parent triarylmethane compounds possess weaker activity.

Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics.

Amphotericin B (AmB, ) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties.

Synthesis and antimicrobial activity of 3,4-bis(arylthio)maleimides.

A series of 3,4-bis(arylthio)maleimides were synthesized and their antimicrobial activity was evaluated against Gram-positive and Gram-negative bacteria, including multidrug resistant (MDR) strains and some fungi. Most compounds turned out to be highly active, activity being dependent on substituents on phenyl rings.

Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides.

One of the promising directions of the combined approach is the design of dual-acting antibiotics - heterodimeric structures on the basis of antimicrobial agents of different classes. In this study a novel series of azithromycin-glycopeptide conjugates were designed and synthesized. The structures of the obtained compounds were confirmed using NMR spectroscopy and mass spectrometry data including MS/MS analysis.

Synthesis and evaluation of biological activity of benzoxaborole derivatives of azithromycin.

Novel benzoxaborole derivatives of azithromycin in which benzoxaborole residue is attached to the 4″-hydroxy-group of azithromycin have been synthesized. Antibacterial activity of synthesized derivatives in comparison with azithromycin was tested on a panel of Gram-positive and Gram-negative bacterial strains. All the investigated compounds demonstrated broad spectrum of antibacterial activity being in general more active against Gram-positive strains.

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties.

Purpose: Development of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions.

Methods: Semisynthetic glycopeptides 3-6 were synthesized from vancomycin (1) or eremomycin (2) by the condensation with pyrrolidine or piperidine. The minimum inhibitory concentration (MIC) for the new derivatives was measured by the broth micro-dilution method on a panel of clinical isolates of Staphylococcus and Enterococcus.

Two approaches to the use of benzo[c][1,2]oxaboroles as active fragments for synthetic transformation of clarithromycin.

Clarithromycin (active against Gram positive infections) and 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole derivatives (effective for Gram negative microbes) are the ligands of bacterial RNA. The antimicrobial activities of these benzoxaboroles linked with clarithromycin at 9 or 4″ position were compared. Two synthetic pathways for these conjugates were elaborated.

Synthesis and Antibacterial Activity of Quaternary Ammonium 4-Deoxypyridoxine Derivatives.

A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant strains with MICs in the range of 0.5-2 g/mL, exceeding the activity of miramistin.

Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group.

A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10.

Synthesis, anti-MRSA, and anti-VRE activity of hemin conjugates with amino acids and branched peptides.

The increasing prevalence of antibiotic-resistant bacterial strains has necessitated the synthesis of novel antibacterial agents. It was previously shown that naturally occurring metalloporphyrin hemin possesses dark antibacterial activity against Gram-positive bacteria. To improve hemin antibacterial activity, we synthesized a number of hemin conjugates with amino acids and branched peptides.

Modification of olivomycin A at the side chain of the aglycon yields the derivative with perspective antitumor characteristics.

A novel way of chemical modification of the antibiotic olivomycin A (1) at the side chain of the aglycon moiety was developed. Interaction of olivomycin A with the sodium periodate produced the key acid derivative olivomycin SA (2) in 86% yield. This acid was used in the reactions with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate (PyBOP) or diphenylphosphoryl azide (DPPA) to give corresponding amides.

N'-(alpha-aminoacyl)- and N'-alpha-(N-alkylamino)acyl derivatives of vancomycin and eremomycin. II. Antibacterial activity of N'-(alpha-aminoacyl)- and N'-alpha-(N-alkylamino)acyl derivatives of vancomycin and eremomycin.

The antibacterial activities of the series of novel N'-(alpha-aminoacyl)- and N'-alpha-(N-akylamino)acyl derivatives of eremomycin and vancomycin containing hydrophobic moieties have been investigated. The N'-(N-alkylglycyl) derivatives of vancomycin are more active against vancomycin-susceptible staphylococci and enterococci and glycopeptide intermediate-resistant Staphylococcus aureus (GISA) than the corresponding eremomycin derivatives, but except for N'-[N-(p-octyloxybenzyl)glycyl-vancomycin] (28) and N'-[N-(p-octyloxybenzyl)-L-alanyl-vancomycin (33)--they are less active against glycopeptide-resistant enterococci (GRE). Derivatives 28 and 33 are the most active compounds (MIC's for glycopeptide-sensitive staphylococci and enterococci are 0.

Structure-activity relationship studies of a series of antiviral and antibacterial aglycon derivatives of the glycopeptide antibiotics vancomycin, eremomycin, and dechloroeremomycin.

N-(adamantyl-1)methyl, N-(adamantyl-2), and N-(omega-aminodecyl) amides of vancomycin, eremomycin, and dechloroeremomycin aglycons and their des-(N-Me-D-Leu) derivatives were synthesized and their antibacterial and anti-HIV activities were investigated. Carboxamides with an intact peptide core demonstrated activity against glycopeptide-susceptible and -resistant bacteria (1-32 microM). N-(adamantyl-1)methylcarboxamide of eremomycin aglycons had good antiretroviral activity (1.

Synthesis and mode of action of hydrophobic derivatives of the glycopeptide antibiotic eremomycin and des-(N-methyl-D-leucyl)eremomycin against glycopeptide-sensitive and -resistant bacteria.

Des-(N-methyl-D-leucyl)eremomycin was obtained by Edman degradation of eremomycin. Derivatives with a hydrophobic substituent at the exterior of the molecule were then synthesized, and their antibacterial activities were compared with similar derivatives of eremomycin. Comparison of derivatives of eremomycin containing the n-decyl or p-(p-chlorophenyl)benzyl substituent in the eremosamine moiety (N') and n-decyl or p-(p-chlorophenyl)benzylamides with similar derivatives of eremomycin possessing the damaged peptide core (a defective binding pocket) showed that compounds of both types are almost equally active against glycopeptide-resistant strains of enterococci (GRE), whereas eremomycin derivatives are more active against staphylococci.