Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a-became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics.The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4Љ-hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4Љ-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides. Beckmann rearrangement of some 16-membered macrolide oximes yielded only 17-membered lactams, which were less active than starting macrolides, and could not be reduced to amines.Intramolecular rearrangement of azalide imino-ethers yielded 13-membered azalides. Some new 11a-azalides were obtained after oxidative cleavage of some 16-membered macrolides and additional cyclisation.
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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