Article

Design, Molecular Docking, Synthesis and Preliminary Evaluation of the Antimicrobial Activity and Stability against β-lactamases of Dipeptides Linked to Cephalexin

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Abstract

Bacterial infections have a large effect on public health. Some bacteria are innately resistant to certain classes of antibiotics, either because they lack the target or are impermeable to the drug. Others are innately susceptible but develop resistance by one of a growing variety of mechanisms. Synthesis of new derivatives of cephalexin that may have improved antibacterial, broader spectrum of activities, resistance against certain β-lactamases and/or pharmacokinetic properties. These derivatives include the incorporation of certain dipeptides at the amino group of cephalexin molecule. The dipeptides to be used are: valine-boc-tryptophan, alanine-boc-tryptophan, valine- boc-histidine, alanine-boc-histidine. The incorporation of dipeptide moiety on the acyl side chain very close to β-lactam ring may widen the spectrum of activity. This chemical addition act as isosteric group to the alkoximino that protect Beta lactam ring from bacterial beta lactamase enzyme. These new derivatives were successfully synthesized with reasonable yields show some resistance against β-lactamases and improve the pharmacokinetic properties. This approach may give new life for old drugs namely, cephalosporins and penicillin's that contain amino group at the acyl side chain close to β-lactam ring. The chemical structures of these derivatives were confirmed by infrared (IR), proton nuclear magnetic resonance (HNMR) spectroscopy and elemental analyses, molecular docking, Swiss ADME software. All the synthesized compounds were subjected for preliminary evaluation of antimicrobial activity using well diffusion method, against certain microbes.

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