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

Abstract

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.

Structure elucidation, complete NMR assignment and PM5 theoretical studies of new hydroxy‐aminoalkyl‐α,β‐unsaturated derivatives of the macrolide antibiotic josamycin

“…The configuration of C(2) C(3) bond is similar to the configuration of E,E-diene moiety in the other part of the aglycone, concluded from the coupling constants 3 J H10,H11 and 3 J H12,H13 ∼ 15 Hz (Table 1). The formation of additional unsaturated system in the aglycone is also well reflected in the 13 than those found in the spectrum of 1 (Table 2), in the range characteristic of the carbon atoms signals of α,β-unsaturated lactones. [34,35] The π -electron coupling between C(2) C(3) bond and the carbonyl C(1) O group within the structures of 2-5 is confirmed also by FT-IR spectra (Fig.…”

“…13 C resonances the DEPT spectra were taken. 2D COSY and NOESY spectra were acquired in the magnitude mode with the gradient selection method and with spectral widths of 6562 Hz for both dimensions.…”

“…These structural changes within 16-membered macrolides involving e.g. insertion of heteroatoms like nitrogen in the macrocyclic aglycone part, [10,11] replacement of diene moiety with amine or carbamate moieties, [12] removal of one of the sugars attached to aglycone, [13] inversion of configuration at carbon atoms of aglycones [14] or redistribution of diene fragments by the scission of carbon atoms [15] have been realised on the way of various chemical reactions yielding new 14-, 15-and 16-membered macrolide analogues like azalides or ketolides of important biological properties and increased biological stability. Recently, also 16-membered macrolides like leucomycin A 7 have been modified at C-3 position by means of the Heck reaction yielding compounds of improved antibacterial activity against important pathogens including erythromycinresistant Strep.…”

Amino Alcohols in Organocatalysed Acylation and Deacylation: The Effect of Dialkylamino Substituents on the Rate

“…Based on the high reactivity of amino alcohols, selective acylation/deacylation can be realised. [11,12] In the case of the more sensitive aldehyde desmycosin (15), its C-17 and C-19 hydroxy groups on the mycaminose sugar residue are adjacent to a dimethylamino group, hence they should have higher reactivity than C-3 and C-24-OH towards acylation. For a demonstration, 15 was treated with excess butyric anhydride (4 equivs.)…”

Od vitamina do antibiotika – sjećanja jednog kemičara II. dio

“…8,9 Započeli smo s 8a-i 9a-laktamima, 10 sintezom cikličkih karbamata 7 te urea, 11 jer njihovi acilidi nisu bili sintetizirani a ni općom formulom patentno zaštićeni. To sam otkrio 1998. godine zahvaljujući sudjelovanju u San Diegu na ICAAC-u (Interscience Conference of Antibacterial Agents and Chemotherapy), na koje nas je odveo veteran tih godišnjih skupova Wolfgang Schönfeld.…”