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

• Published in: Journal of medicinal chemistry 2004-01, Vol.47 (2), p.411-431
• Main Authors: Mutak, Stjepan, Maršić, Nataša, Kramarić, Miroslava Dominis, Pavlović, Dražen
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Biological Availability; Colony Count, Microbial; Drug Resistance, Bacterial; Erythromycin - pharmacology; Medical sciences; Mice; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution; Tylosin - analogs & derivatives; Tylosin - chemical synthesis; Tylosin - chemistry; Tylosin - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0308951

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, α,β-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 MLSB-resistant strains that were inducibly resistant, but not those constitutively resistant to erythromycin.