Design, Molecular Docking, Synthesis, and Antimicrobial Evaluation of new Dipeptide derivatives of Ceftizoxime sodium

Abstract

Newer cephalosporins that can be orally administered with significant oral bioavailability and resist β-lactamases are continuously and significantly requested. A method of using a potent third-generation cephalosporin, ceftizoxime, was suggested to synthesize new dipeptide derivatives. These derivatives were successfully synthesized by linking a dipeptide moiety, which includes L-Tryptophan-L-valine, L-Tryptophan-L-alanine, L-Tryptophan-L-histidine, and L-Tryptophan-L-phenylalanine as dipeptides to the aminothiazole moiety of ceftizoxime by an amide bond. Their chemical structures were confirmed by spectral analysis, including 1H-NMR,13CNMR, and FT-IR spectroscopy. Molecular docking for these new derivatives was performed on penicillin-binding proteins (PBPs) type 2a (3ZG0) of Methicillin-resistant Staphylococcus aureus, type 2X (5OJ0) of Streptococcus pneumonia and type 1b (5HLA) of E. coli, and has recorded higher affinity binding represented as PLP fitness on target enzymes. The binding scores were significant and may indicate better antimicrobial activities when compared with ceftizoxime. This improvement in affinity binding can be explained by the presence of indole and/or imidazole moieties in those derivatives. The indole and imidazole moieties are actual pharmacophores with various biological activities and may contribute to affinity binding, and the derivatives are considered molecular hybrids. Furthermore, a preliminary evaluation of the antibacterial activity of the synthesized derivatives was performed against two significant bacterial species (MRSA and E. coli), which showed better activity in compression to ceftizoxime. Moreover, the derivatives were tested on the protein oligopeptide (POT) family system and have recorded very interesting results for possible oral absorption when compared with Ceftizoxime, Val-acyclovir, and Val-Val-Acyclovir, as reference drugs. The Swiss ADME server was also used to analyze the pharmacokinetic characteristics and identify those likely to be absorbed orally.