Novel semisynthetic oxo and alkyl macrolide antibacterials and related derivatives

Fishman, A. G.; Mallams, Alan K.; Puar, Mohindar S.; Rossman, Randall; Stephens, Richard

doi:10.1039/p19870001189

Cited by 13 publications

(8 citation statements)

References 19 publications

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“…The structure of all novel compounds was confirmed by IR, MS, and NMR spectroscopic methods. Complete and unambiguous assignments for all 1 H and 13 C resonances could be achieved on the basis of chemical shift considerations, coupling information (APT 15 and gated decoupled 13 C NMR spectra), and COSY-45, 29 HMQC, 30 and 1D-HETCOR 31 spectra as well as on long-range INEPT experiments 32 with selective DANTE excitation.…”

Section: Methodsmentioning

confidence: 99%

“…This takes into account that the core structure of a compound class contributes to the pharmacological profile in addition to the effect it mediates by directing the spatial arrangement of the pharmacophoric substituents. Therefore, the following scaffolds were used for the construction of the library: 2‘,4‘,4‘ ‘-tri- O -acetyldesmycosin ( 7 ), − 10,11,12,13-tetrahydrodesmycosin ( 8, THD), 4‘-deoxy-THD ( 9 ), 3- O -acetyldesmycosin ( 10 ), tylosin ( 1 , T), THT ( 11 ), 2,3-anhydrodesmycosin ( 12 ), 2,3-didehydrodesmycosin ( 13 ), and 2,3-didehydro-THD ( 14 , Figure ) . A simple straightforward structure such as 7 should allow optimization of potency, by parallel or classical synthesis, for example, by formation of the ester bond or double bond by classical carboxylic acid−alcohol condensation methods or Wittig reaction, respectively.…”

Section: Chemistrymentioning

confidence: 99%

“…10,11 Acetyl-derived protecting groups were selected for all of these hydroxyl groups, because they can be removed cleanly in one step with aqueous ammonia in methanol. This process basically includes selective acetylation of the protected aldehyde (15) via two-step sequence and starts with the acetylation of the hydroxyl groups on amino sugar D-mycaminose (3). Acetylation of the resulting 2′,4′diacetate ( 16) with acetic anhydride in the presence of a catalytic amount of (dimethylamino)pyridine (DMAP) and triethylamine proceeded selectively at the C-4′′ position of D-mycinose (5) to yield triacetate (17), the substrate for the oxidation.…”

Section: Chemistrymentioning

confidence: 99%

“…24b (minor isomer): FAB-MS m/z 770 (MH + , 63%); UV λmax nm ( ) 278 (32 492); IR (KBr) νmax 3442,2973,2931,1740,1692,1657,1458,1374,1265,1164,1086, 1064 cm -1 ; 1 H NMR (CDCl3) δ 7. 44 (1H,d,J10,11 ) 16.5 Hz),5.94 (1H,d,J10,11 ) 16.5 Hz),5.90 (1H,d,J13,14 ) 10.3 Hz),5.10 (1H,dt,J14,15 ) 10.0 Hz, J15,16b ) 4.0 Hz), 4.78 (1H, d, H-5, J4,5 ) 6.9 Hz), 4.59 (1H, d, H-1′′, J1′′,2′′ ) 7.7 Hz), 4.47 (1H, d, H-1′, J1′,2′ ) 7. 4 Hz),m,, 3.79-3.73 (2H, m, H-3′′, H-2b), 3.61 (3H, s, 3′′-OMe), 3.60-3.50 (5H, m, H-23a, H-5′′, H-5′, H-4, H-2′), 3.49 (3H, s, 2′′-OMe), 3.42 (1H, d, H-2a, J2a,2b ) 16.5 Hz), 3.18 (1H, dd, H-4′′, J3′′,4′′ ) 3.2 Hz, J4′′,5′′ ) 9.6 Hz), 3.10-3.04 (1H, dd, H-4′, J3′,4′ax ) J4′,5′ ) 10.0 Hz; 1H, dd, H-2′′, J1′′,2′′ ) 7.9 Hz, J2′′,3′′ ) 2.9 Hz), 2.99-2.95 (1H, m, H-14), 2.51 (6H, s, NMe2), 2.41 (1H, t, H-3′, J2′,3′ ) J3′,4′ax ) 10.1 Hz), 1.99 (1H, br, H-6), 1.86 (1H, m, H-19b) ), 62.9 (q, 3′′-OMe), 60.3 (s, C-8), 59.6 (q, 2′′-OMe), 46.9 (t, C-2), 43.9 (d, C-14), 41.7 (q, NMe 2), 41.3 (d, C-6), 37.1 (t, C-19), 37.0 (t, C-7), 35.7 (d, C-4), 26.1 (t, C-16), 18.2 (q, Me-C-5′), 17.7 (q, Me-C-5′′), 17.5 (q, Me-21), 17.1 (q, Me-18), 12.4 (q, Me-22), 9.7 (q, Me-17).…”

Section: Synthesis Of 4′′-o-acetyl Bicyclic Aldehyde (23)mentioning

confidence: 99%

“…33 (1H, d, H-11, J10,11 ) 15. 4 Hz),6.93 (1H,dt,J20,20′ ) 15.8 Hz,J19,20 ) 7.8 Hz), 6.28 (1H,d,J10,11 ) 15.4 Hz),5.90 (1H,d,J13,14 ) 10.9 Hz), 5.84 (1H,d,J20,20′ ) 15.8 Hz),4.97 (1H,dt,J14,15 ) 10.0 Hz, J15,16b ) 3.9 Hz), 4.90 (1H, br, H-2′), 4.78 (1H, br, H-4′), 4.63 (1H, d, H-1′′, J1′′,2′′ ) 8.0 Hz), 4.44 (1H, dd, H-4′′, J3′′,4′′ ) 2.5 Hz, J4′′,5′′ ) 9.9 Hz), 4.20-4.05 (3H, m, COOCH2CH3, H-1′), 3.99 (1H, dd, H-23b, J23a,23b ) 9. 5 Hz,J14,23b ) 4.4 Hz),m,m,3.55 (1H,dd,J23a,23b ) 9.5 Hz, J14,23a ) 4.7 Hz), 3.52 (3H, s, 3′′-OMe), 3.44 (3H,s,m,, H-5′), 3.05 (1H, dd, H-2′′, J1′′,2′′ ) 8.0 Hz, J2′′,3′′ ) 2.…”

Section: Synthesis Of 4′′-o-acetyl Bicyclic Aldehyde (23)mentioning

confidence: 99%

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Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

et al. 2003

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A series of 20-O-substituted and 3,20-di-O-substituted derivatives of desmycosin were synthesized and their biological properties were evaluated. In particular, we have synthesized numerous side chain modified analogues of desmycosin as well as some analogues possessing a combination of modified side chain and alternative C-3 substituents. Thus, alpha,beta-unsaturated analogues of desmycosin (2), tylosin (1), 10,11,12,13-tetrahydrotylosin (11), and 2,3-didehydrodesmycosin (13) were prepared from the corresponding aldehydes by a Wittig reaction with the stabilized ylides (a-d), generating a trans-double bond, followed by modified Pfitzner-Moffat oxidation of the C-3 hydroxyl group. To evaluate the importance of the C-3 position of desmycosin for biological activity, the C-3 substituted derivatives were synthesized by a standard sequence of protective group chemistry followed by Wittig reaction and esterification as the key steps. For the attachment of the C-3 ester functionality, a mixed anhydride protocol was adopted. Reaction proceeded smoothly to give corresponding esters in yields ranging from 70 to 80%. Base- and acid-catalyzed rearrangement products including desmycosin 8,20-aldols (24a and 24b) and desmycosin 3,19-aldol (25) are also described. Parallel array synthesis and purification techniques allowed for the rapid exploration of structure-activity relationships within this class and for the improvement in potency. In vitro evaluation of these derivatives demonstrated good antimicrobial activity against Gram-positive bacteria for most of the compounds. The present derivatives of 16-membered macrolides were active against MLS(B)-resistant strains that were inducibly resistant, but not those constitutively resistant to erythromycin.

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Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Synthesis Of 4′′-o-acetyl Bicyclic Aldehyde (23)mentioning

confidence: 99%

Section: Synthesis Of 4′′-o-acetyl Bicyclic Aldehyde (23)mentioning

confidence: 99%

See 3 more Smart Citations

Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

et al. 2003

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Thiolacetic Acid

Phillips

2001

Encyclopedia of Reagents for Organic Synthesis

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Macrolides

Kirst¹

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Macrolide antibiotics are well‐established antimicrobial agents in both clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram‐positive organisms, Mycoplasma species, and certain susceptible gram‐negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone ring. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be 12‐, 14‐, or 16‐membered. Naturally occurring 14‐membered macrolides include erythromycin A (C 37 H 67 NO 13 ), erythromycin B (C 37 H 67 NO 12 ), erythromycin C (C 36 H 65 NO 13 ), erythromycin D (C 36 H 65 NO 12 ), erythromycin F (C 37 H 67 NO 14 ), and erythromycin E (C 37 H 65 NO 14 ), as well as others. Erythromycin has been the principal subject of modification of 14‐membered macrolides; some of the derivatives of erythromycin and oleandomycin include 2′‐ O ‐acetylerythromycin (C 39 H 69 NO 14 ), 2′‐ O ‐propionylerythromycin (C 40 H 71 NO 14 ), erythromycin ethyl carbonate (C 40 H 71 NO 15 ), and others. 16‐Membered macrolides are divided into leucomycin‐ and tylosin‐related groups, which differ in the substitution pattern of their aglycones. Natural products include leucomycin A 1 (C 40 H 67 NO 14 ), leucomycin A 5 (C 39 H 65 NO 14 ), leucomycin A 7 (C 38 H 63 NO 14 ), midecamycin A 2 (C 42 H 69 NO 15 ), and others. A second large group of 16‐membered macrolides differs from the leucomycins in the substitution pattern of the aglycone. One difference is a methyl or hydroxymethyl group at C‐14. The most prominent member of this group is tylosin, an important veterinary antibiotic produced by S. fradiae. Tylosin and related products include tylosin (C 46 H 77 NO 17 ), relomycin (20‐dihydrotylosin) (C 46 H 79 NO 17 ), macrocin (C 45 H 75 NO 17 ), O ‐demethylmacrocin (C 44 H 73 NO 17 ), and others. Other macrolides have been made by chemical, bioconversion, or genetic manipulations which represent hybrids of structures within the 14‐membered family, within the 16‐membered family, or between the two families. The advent of molecular biology has opened new possibilities for producing hybrid macrolides. Genetic manipulations of biosynthetic pathways in macrolide‐producing microorganisms complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram‐positive bacteria, Mycoplasma species, and certain gram‐negative and anaerobic bacteria. Susceptible gram‐positive bacteria include many species of Staphylococcus and Streptococcus; susceptible gram‐negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis (formerly Branhamella ), and Haemophilus ducreyi. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross‐resistance to lincosamide and streptogramin B antibiotics (MLS‐resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolides are obtained by controlled submerged aerobic fermentations of soil microorganisms. Although species of Streptomyces have dominated, species of Saccharopolyspora, Micromonospora, and Streptoverticillium are also well represented. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. Relatively few macrolides are used in veterinary medicine. The most important is tylosin (Tylan, Elanco Products), which is used to control chronic respiratory disease caused by Mycoplasma gallisepticum in poultry.

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Novel semisynthetic oxo and alkyl macrolide antibacterials and related derivatives

Cited by 13 publications

References 19 publications

Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

Semisynthetic Macrolide Antibacterials Derived from Tylosin. Synthesis and Structure−Activity Relationships of Novel Desmycosin Analogues

Thiolacetic Acid

Macrolides

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