Study On Structural Transformation And Structure - Activity Relationship Of 16 - Membered Macrolide - Associated Dicarboxylic Acid With Biological Activity As Guidance

The16-membered macrolides, such as josamycin and tylosin, constitute an important class of useful antibiotics of the macrolide family, which were studied relatively backward compared that with14-membered macrolides. They offer some advantages over the14-membered macrolides. These advantages include better gastrointestinal tolerance, lack of drug-drug interactions, and the activity against resistance expressing strains.During our efforts to develop novel macrolides active against bacteria, we became interested in josamycin primarily because its activities are not affected by mef-resistance. Josamycin is an important drug used to treat Gram-positive and mycoplasma infections. This macrolide antibiotic is composed of a16-membered lactone ring and an unusual disaccharide D-mycaminosyl-L-mycarose at C-5position, which is oriented similarly to the5-O-desosamine of14-membered macrolides. Furthermore, the mycarose extends toward the peptidyl transferase center (PTC), making additional interactions at G2505and U2506. The16-aldehyde group of josamycin is also important to the activity, which will form a covalent bond with the N6of A2103(2062) when macrolide binds the ribosome.In this paper, we intended to find some new molecule entities to improve antibacterial activity both sensitive pathogens and resistant ones, and the acid stability of16-membered macrolide and study the preliminary SAR.1, Synthesis and Antibacterial Activity of a Series of Novel9-0-Acetyl-4’-Substituted16-Membered Macrolides Derived from JosamycinA series of novel9-O-acetyl-4’-substituted16-membered macrolides derived from josamycin has been designed and synthesized by cleavage of the mycarose of josamycin and subsequent modification of the4’-hydroxyl group. These derivatives were evaluated for their in vitro antibacterial activities against a panel of S. aureus and S. epidermidis.15(4’-O-(3-phenylpropanoyl)-9-O-acetyl-desmycarosyl josamycin) and16(4’-O-butanoyl-9-O-acetyl-desmycarosyl josamycin) exhibited comparable activities to josamycin against S. aureus (MSSA) and S. epidermidis (MSSE).2, Synthesis an antibacterial Activity of a Series of Novel Bearing A6-aza-side chain Macrolides Derived from JosamycinA series of novel16-membered macrolides bearing an arylalkyl-type side chain at6-position was designed and synthesized by reductive animation reaction. They were evaluated for their in vitro antibacterial activities against a panel of respiratory pathogens. All the compound showed none or weak activity against respiratory pathogens.3, Synthesis an Antibacterial Activity of a Series of Novel α,β-unsatureated acid derivatives from9-O-acetyl-desmycarosyl josamycinA series of novel16-membered macrolides of α,β-unsaturated acid derivatives bearing an arylalkyl-type side chain from9-O-acetyl-desmycarosyl josamycin was designed and synthesized by short steps. They were evaluated for their in vitro antibacterial activities against a panel of respiratory pathogens. The compounds43b (benzyl ester) and43e (naphthalen-2-ylmethyl ester) exhibited comparable activity against a panel of respiratory pathogens, especially to resistant strains.4, Synthesis an Antibacterial Activity of a Series of Novel α,β-unsatureated carbonyl derivatives from josamycinA series of novel16-membered macrolides of α,β-unsaturated carbonyl derivatives bearing an arylalkyl-type side chain from josamycin was designed and synthesized by short steps. They were evaluated for their in vitro antibacterial activities against a panel of respiratory pathogens.5, Synthesis and Antibacterial Activity of a Series of Novel4’-Substituted16-Membered Macrolides derived from9-O-acetyl-desmycarosyl-α, β-unsatureated acid esterA series of novel4’-Substituted16-Membered Macrolides derived from9-O-acetyl-desmycarosyl-α,β-unsatureated acid ester bearing an arylalkyl-type side chain was designed and synthesized by short steps. They were evaluated for their in vitro antibacterial activities against a panel of respiratory pathogens.6, Synthesis and Antibacterial Activity of two Nitro-glycoside josamycin with α,β-unsatureated acid estersTwo of nitro-glycoside josamycin with α,β-unsatureated acid esters were designed and synthesized by short steps.