Synthesis of Nα-protected aminoacid/peptide Weinreb amides employing N,N′-carbonyldiimidazole as activating agent; studies on docking and antibacterial activities

Abstract

An efficient method for the synthesis of Nα-protected amino/ peptide Weinreb amides (N-methoxy-N-methylamides) employing N,N′-carbonyldiimidazole (CDI) has been achieved. Nα-protected amino/peptide acids were treated with N,N′-carbonyldiimidazole, followed by the addition of N,O-dimethylhydroxylamine hydrochloride salt to yield the desired compounds. The synthesized compounds were mainly gums, a few were solids, after the simple workup, and were characterized by IR, 1H NMR, 13C NMR and HRMS. The Weinreb amides were subjected to in silico studies, to predict the preferred orientation and binding affinity between the molecules using scoring functions. The ligand N-Fmoc-L-Phe-N(OCH3)CH3 showed minimum binding energy -29.85 kcal/mol with Escherichia coli and the ligand N-Fmoc-L-Ala-N(OCH3)CH3 showed minimum binding energy -24.79 kcal/mol with Pseudomonas aeruginosa, -25.01 kcal/mol with Staphylococcus aureus. Based on the minimum binding energies, antibacterial activities have been conducted for a few of the synthesized compounds.