Synthesis of boron cluster analogs of penicillin and their antibacterial activity

Abstract

Antimicrobial resistance (AMR) is an exceptional increasing challenge for human health; it is urgently need to develop novel leads that can be developed to clinically useful drugs. The idea to modify old class of antibiotics that has been a cornerstone of medical has been dramatically refreshed searching for ways to overcome antibiotic-resistant bacteria. A very interesting development is the implementation of carboranes in design of pharmacologically active molecules. A series of novel penicillin G analogs bearing lipophilic 1,2-dicarba-closo-dodecaborane (ortho-carborane), 1,7-dicarba-closo-dodecaborane (meta-carborane), or 1,12-dicarba-closo-dodecaborane (para-carborane) boron clusters, instead of the phenyl ring, were synthesized. The boron-cluster penicillin G analogs were obtained via amidation of 6-aminopenicillanic acid (6-APA) with N-succinimidyl active esters containing ortho-, meta-, or para-carborane Alternatively, analogs containing ortho- or para-carborane were synthesized using ortho- or para-carborane cluster acid chlorides. The compounds thus obtained were tested in vitro against gram-positive bacteria Staphylococcus aureus and gram-negative bacteria Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumanii, and Pseudomonas aeruginosa. The most potent inhibitor of gram-positive bacterial growth was compound 9, bearing a para-carborane cluster. Compounds 7 and 8 bearing ortho- or metha-carborane, respectively, were less active against S. aureus.