Synthesis and Antibacterial Activities of Novel Antibiotics. رسالة دكتوراة

Abstract

One of the biggest health threats in the world is antibiotic resistance, and patient non-compliance contributes to this issue because of the bad taste of oral antibiotics such as azithromycin and clarithromycin. The purpose of this work was to overcome these difficulties, by synthesizing and assessing new prodrugs and derivatives of macrolide (azithromycin, clarithromycin) and penicillins (amoxicillin, 6-aminopenicillanic acid) antibiotics. The major purposes were to cover the unpleasant macrolides taste and to improve the antimicrobial effect of beta-lactams. The parent antibiotics were reacted with five linkers, including, n-acetylbenzenesulfonyl chloride, p- nitrobenzoyl chloride, p-toluenesulfonyl chloride, 3,5-dinitrobenzoyl chloride and p- nitrobenzenesulfonyl chloride to produce 20 new derivatives. The synthesized products were identified by FTIR, NMR and Mass Spectrometry. Hydrolytic stability of Macrolide prodrugs were evaluated at pH 2.2, pH 5.5 and pH 7.4. Molecular docking in silico was conducted on penicillin derivatives to determine the interaction of the penicillin derivatives with penicillin-binding proteins (PBPs), and the in vitro antimicrobial activity of each derivative of penicillin against Escherichia coli, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Staphylococcus aureus was assessed by determining the MIC, and IC50. The outcomes have shown that it was possible to produce the twenty derivatives successfully. The hydrolysis research indicated that the azithromycin derivative compound 5 exhibited optimal prodrug properties as it was easily transformed to the active parent drug with full pH-dependent hydrolysis. A number of derivatives had a marked improved antimicrobial activity as compared to the parent V drugs. Markedly, compounds 4 and 10 were found to be much stronger against P. aeruginosa, compound 8 was found to be highly active against S. pneumoniae and S. aureus compound 8 and the obvious wide-spectrum winner, whilst compounds 12 and 17 were found to be extremely active against P. aeruginosa and S. aureus more than the parent amoxicillin and consider abroad spectrum derivatives. This study was able to come up with promising antibiotics derivatives. One possible remedy to enhance patient compliance is the use of taste-masked pro drug forms of macrolide, especially com pound 5. Moreover, the increased efficacy of certain derivatives of beta-lactam against pathogen resistance underscores their being the next generation therapeutic agents.