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Thiazole peptide GE2270 A (1) possesses potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus (S. aureus, MRSA; MIC(90)=0.06 microg/mL) and vancomycin resistant Enterococcus spp. (VRE; MIC(90)=0.03 microg/mL); however its poor aqueous solubility has prohibited its development for the clinical treatment of infections. An integrated combinatorial and medicinal chemistry program was employed to identify derivatives of 1 that retain activity but possess greatly enhanced aqueous solubility.

Controlled acid hydrolysis of compound 2 resulted in the selective opening of the macrocycle while in basic condition a retro-aldol reaction occurred at the level of phenylserine thiazole. Compound 2 can be easily prepared from the natural antibiotic MDL 62,879. All the compounds prepared resulted less active than MDL 62,879.

Reaction of teicoplanin glycopeptides with sodium borohydride in aqueous ethanol solutions produced open pentapeptide derivatives in which the amide bond between amino acids 2 and 3 was hydrolyzed and the carboxyl group of amino acid 2 was reduced to a primary alcohol. Other glycopeptides of the dalbaheptide family, such as vancomycin, ristocetin, and A-40,926, underwent selective reductive hydrolysis (RH) of the heptapeptide backbone at the same position as in teicoplanins, while antibiotic A-42,867 and vancomycin hexapeptide were resistant. Also, teicoplanin and vancomycin were resistant to RH-treatment when the N-terminus was protected as carbamate. In contrast, open hexapeptides in which the 1,2-peptide bond was hydrolyzed and the carboxyl group of amino acid 1 was reduced to hydroxymethyl were obtained from carbamate derivatives of sugar-free compounds deglucoteicoplanin (TD) and vancomycin−aglycon (VA) under RH-conditions. Limited to BOC or CBZ-TD, the 3,4-amide bond was also affected. A possible RH...

Starting from the antibiotic A-40926 and the aglycone of A-40926 a series of compounds were prepared by modifying the free functionalities. Their antimicrobial activity was determined, particularly against Neisseria gonorrhoeae, against which A-40926, unlike other natural glycopeptides, is active. Improved in vivo activity was displayed by the monomethyl ester of A-40926 esterified at the carboxyl group of the N-acylamino-glucuronyl moiety.

Removal, by selective reduction, of the acetylglucosamine from teicoplanin A2-2 (CTA/2) produced the 34-de(acetylglucosaminyl)-34-deoxy pseudoaglycone (II). This compound was more active in vitro than CTA/2 against coagulase-negative staphylococci (CNS). Amide derivatives obtained by condensation of the carboxyl group of II with primary amines were particularly active against Streptococcus pyogenes and had some in vitro activity against VanA enterococci highly resistant to both teicoplanin and vancomycin. Among them, a carboxamide (VII) with a branched tetramine also had better activity than the corresponding amide of teicoplanin against CNS. In contrast, the dimethylamide (VIII) of II had little activity against VanA enterococci. While the overall structure of the heptapeptide backbone of the secondary carboxamides of II is the same as in CTA/2 and its amide derivatives, in deoxy pseudoaglycone II and its tertiary amide VIII the 51,52-peptide bond undergoes a conformational change from the original cisoid to the transoid orientation. This difference between the secondary amides of II and dimethylamide VIII is reflected in their different antibacterial spectrum. The direct synthesis of the amides of deoxy pseudoaglycone II from parent CTA/2-amides by reaction with sodium borohydride is also described.

When Actinoplanes strain ATCC 33076, the producer of A-16686 A1, A2 and A3 complex, is fermented in a suitable medium three additional factors, designated A' 1, A' 2 and A' 3 are produced. These were isolated and characterized, and were shown to differ from the parent components of the original complex by lacking one mannose unit. Bioconversion of A factors into A' factors was achieved by incubation with the mycelium of Actinoplanes ATCC 33076. Factor A' 2 has better antibacterial activity than A2 against some bacteria.

Influenza types A and B both cause serious disease in man; vaccines are in use but must be reformulated each year in response to antigenic variation and are frequently ineffective against new influenza variants. Influenza viruses are enveloped RNA viruses which contain two major surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA, EC 3.2.1.18). These proteins are essential for infection and offer potential targets for antiviral drug development. Based upon the knowledge of the most important steps of the whole interaction between virus and host cell, the main purpose of our research was to find a sialic acid analogue for increasing the affinity of the sialic acid cell receptor analogue to the principal binding site of HA. A series of sialic acid analogues were prepared and their structures were designed with the goal to have molecules able to saturate the HA receptor and thereby be potentially useful as anti-influenza drugs.

Purpuromycin (1) is an antibiotic with a broad spectrum of antimicrobial activity, encompassing bacteria, fungi, and protozoa, particularly those involved in vaginal infections. With the aim of enhancing the solubility and reducing the serum binding, a chemical program of modifications was undertaken on the natural compound, and a new interesting series of derivatives at the naphthoquinone system was synthesized and evaluated as potential topical agents for vaginal infections. In particular three semisynthetic derivatives, 7'-amino (8a), 7'-methylamino (8b), 7'-ethylamino (8c), of 7'-demethoxypurpuromycin seemed to be the most promising. They were tested for in vitro activity against three of the most important vaginal pathogens and showed activity similar to that of purpuromycin against Candida isolates while they were significantly more active against Trichomonas vaginalis and Gardnerella vaginalis, which are cultured in media containing blood or serum. This is probably due to the fact that the activity of the derivatives is less antagonized by these supplements than that of purpuromycin.

New N-acyl derivatives of 1-N-desmethyl goldinamine were obtained from degradation of kirromycin. Periodate-oxidation of these derivatives provided new aldehydic fragments that were further elaborated. Both N-phenyl ureido and N-phthalimido derivatives of 1-N-desmethyl goldinamine are able to inhibit bacterial protein synthesis in cell-free assay and are active against whole microorganisms, although with lower potency than kirromycin. The derivatives from the aldehydic fragments are totally inactive.

An Edman degradation of the antibiotic eremomycin aglycone produced the corresponding hexapeptide, which was aminoacylated with D-lysine, D-histidine or D-tryptophan derivatives to give new heptapeptide analogs of the eremomycin aglycone. The aminoacylation of the eremomycin aglycone produced an octapeptide analog. The substitution of D-lysine for the N-terminal N-methyl-D-leucine does not seriously affect the in vitro antibacterial properties of the eremomycin aglycone whereas the heptapeptides with the N-terminal D-tryptophan or D-histidine moieties and the octapeptide with the N-terminal D-lysine are practically devoid of the antibacterial properties.

The synthesis and biological properties of a series of N63-carboxamides of 15-N-alkylated derivatives of teicoplanin A2 (CTA) and its aglycone (TD) are described. Among the compounds, those carrying hydrophilic groups or ionizable amino functions on the N15-alkyl chain are more soluble in water than parent N15-methylated or unmodified amides. Selected compounds were more active in vitro than CTA or TD, and a few of them were also slightly more efficacious in vivo than the parent antibiotics in streptococcal septicemia in the mouse. Their degree of activity varied with the structure and length of the N15-alkyl chains.

Basic carboxamides of teicoplanin A2 (CTA) and its aglycon (TD) are prepared by condensation of the 63-carboxyl function of these antibiotics with linear or branched polyamines. The antimicrobial activities of some of the resulting compounds were better than those of the unmodified antibiotics. The presence of more than one basic group in the amidic chain enhanced the in vitro activity of some TD-amides against Gram-negative bacteria; two of these derivatives were also effective in vivo against Escherichia coli septicemia in the mouse. Among the CTA derivatives, the amide with spermine showed some unexpected in vitro activity against Gram-negatives. Both CTA- and TD-amides with polyamines are very soluble in water over a wide range of pH and are very hydrophilic.

The condensation of the terminal carboxyl group of the deglucoteicoplanin (TD) with various substituted hydrazines produced hydrazide derivatives having different physico-chemical properties. This chemical modification of the carboxyl function does not affect the ability of teicoplanin antibiotics to interfere in bacterial cell-wall synthesis. The antibacterial activity of deglucoteicoplanin hydrazides (V) were found to depend mostly on their ionic character. All the hydrazides were slightly more active than TD on Escherichia coli. Those possessing an additional basic group were more in vitro active than TD against Gram-negative microorganisms. In Experimental Streptococcus pyogenes septicemia in the mouse, basic hydrazides were more active than other derivatives when administered subcutaneously although they are as potent as TD.

Some 13-aza-14-oxo prostaglandin analogues of PGF2 alpha, PGE2 and PGA2 have been synthetized in optically active form, starting from Corey's intermediate and evaluated for antifertility activity in the hamster. The C-15 absolute configuration was established and found critical for the biological activity, but unexpectedly the highest potency was always associated with the 15 epi derivatives. Among the PGF2 alpha analogues the 15 epi derivative was about one tenth as potent as PGF2 alpha. The preparation of a few 16-phenoxy 17,18,19,20 tetranor-derivatives led to more potent compounds with the p-fluorophenoxy analogue having the same potency as PGF2 alpha.

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF2 alpha, -PGE2, and -PGE1 is described. The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra. The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects. Both the C-15 and C-16 configurations were found to be critical for the biological activities. These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action. One of the PGE1 derivatives, 9f(15 alpha, 16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF2 alpha, -PGE2, and -PGE1 is described. The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra. The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects. Both the C-15 and C-16 configurations were found to be critical for the biological activities. These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action. One of the PGE1 derivatives, 9f(15 alpha, 16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.

A series of thiourea and isothiouronium salt derivatives of the aglycone of teicoplanin was prepared by reaction of the terminal amino group with isothiocyanates, followed by S-alkylation of the thiourea compounds. Unexpectedly, the two classes of derivatives show a similar in vitro antibacterial activity against Gram-positive bacteria. Thiourea compounds, due to the lack of a positively charged N-terminus group, have a 10-fold lower binding constant to Ac-D-Ala-D-Ala, a bacterial cell-wall model, than the parent antibiotic and isothiouronium salt derivatives.

N15-Isothiouronium derivatives of teicoplanin and its aglycone submitted to alkaline condition give rise to an intramolecular cyclization. The structures of the new gamma-lactam derivatives were determined by using 1H NMR, IR and fast atom bombardment mass spectra. The cyclization mechanism was interpreted on the basis of the identification of the intermediate structure. The poor in vitro antibacterial activity of the new cyclic compounds and the negligible affinity for the synthetic peptidoglycan model Ac2-L-Lys-D-Ala-D-Ala is probably due to the lack of the N-17 amidic proton and to the lack of the basic character of the nitrogen in position 15.

The replacement of amino acids I and 3 of glycopeptide antibiotics (dalbaheptidcs) with new amino acids or other chemical entities suitable to interact with both glycopeptide-resistant (D-Ala-D-Lactate) and susceptible (D-Ala-D-Ala) targets is one of the chemical strategies currently followed to pursue activity against highly glycopeptide-resistant VanA enterococci while maintaining activity against glycopeptide-susceptible Gram-positive bacteria, particularly methicillin-resistant staphylococci. As a preliminary approach, the substitution of amino acid I of deglucoteicoplanin (TD) with D-lysine or D-methylleucine and of its amino acid 3 with L-phenylalanine or L-lysine was investigated. In this paper, the synthesis and in vitro antibacterial activities of first non-natural dalbaheptide methyl ester aglycons MDL 63,166 (D-Lys 1 -Phe 3 -TD-DHP-Me), MDL 64,945 (D-Lys 1 -Lys 3 -TD-DHP-Me), and MDL 64,468 (D-MeLeu 1 -Lys 3 -TD-DHP-Me) are described. These compounds, which were obtained from intermediate TD-derived tetrapeptide methyl ester (TDTP-Me) according to a 9-step overall procedure, had excellent anti-staphylococcal activity. The most active derivative against staphylococci, MDL 64,945 (MIC: 0.063 μg/ml for S. aureus, S. epidermidis and S. haemolyticus) was inactive against VanA enterococci, while MDL 63,166 and MDL 64,468 were somewhat active against VanA strains of E. faecalis, MDL 64,468 was also moderately active against one VanA isolate of E. faecium and had marginal activity as TD against E. coli.

A series of 7d-aminomethylated derivatives (mono modified) and their amides (double modified) at the amino acid No. 7 of teicoplanin aglycon were prepared with the aim of obtaining activity against vancomycin-resistant VanA enterococci. Among mono modified compounds, the 7d-n-decylaminomethyl derivative was the most active against VanA enterococci (4 micrograms/ml). Amides of the latter with 3-dimethylamino-propylamine or methylamine were found to be up to four times more active against glycopeptide-susceptible Gram-positive bacteria, and up to four times less active against VanA enterococci than the starting compound.