Development of 1,2,4-Oxadiazole Antimicrobial Agents to Treat Enteric Pathogens within the Gastrointestinal Tract

Abstract

Colonization of the gastrointestinal (GI) tract with pathogenic bacteria is an important risk factor for the development of certain potentially severe and life-threatening healthcare-associated infections, yet efforts to develop effective decolonization agents have been largely unsuccessful thus far. Herein, we report modification of the 1,2,4-oxadiazole class of antimicrobial compounds with poorly permeable functional groups in order to target bacterial pathogens within the GI tract. We have identified that the quaternary ammonium functionality of analogue 26a results in complete impermeability in Caco-2 cell monolayers while retaining activity against GI pathogens Clostridioides difficile and multidrug-resistant (MDR) Enterococcus faecium . Low compound recovery levels after oral administration in rats were observed, which suggests that the analogues may be susceptible to degradation or metabolism within the gut, highlighting a key area for optimization in future efforts. This study demonstrates that modified analogues of the 1,2,4-oxadiazole class may be potential leads for further development of colon-targeted antimicrobial agents.

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

“…[ 7 , 8 , 9 , 10 , 11 , 12 ]). The interesting feature of the 1,2,4-oxadiazole moiety from a medicinal chemistry viewpoint is its potential coverage of a broad spectrum of therapeutic areas, including oncology [ 13 , 14 , 15 ], immunology [ 16 ], neurology [ 17 , 18 , 19 , 20 ], infectious diseases [ 21 , 22 , 23 , 24 ], metabolism and endocrinology [ 25 , 26 , 27 , 28 ], urology [ 29 , 30 ], gastroenterology [ 31 ], cardiology [ 32 ], rheumatology [ 33 ], and respirology [ 34 ]. Such versatility of the 1,2,4-oxadiazole motif, in our opinion, is due to its recognition as the hydrolytically stable bioisostere of the amide and ester bonds [ 35 , 36 , 37 , 38 , 39 ].…”

Simple and Efficient Synthesis of Diamino Derivatives of bis-1,2,4-oxadiazole via Tandem Staudinger/aza-Wittig Reaction

“…Oxadiazoles are one of the most important heterocyclic compounds with desirable biological or functional material properties, which are used widely in medicine, pesticidal chemistry and other fields as a stable bioisosterism of esters or amides. As a key member of the oxadiazole family, drugs containing a 1,2,4-oxadiazole core are associated with a diverse range of pharmacological and biological activities, such as anticancer [ 1 , 2 ], antimicrobial [ 3 ], antibacterial activity [ 4 ], anti-inflammatory activity [ 5 ], pesticidal activities [ 6 ] and HDAC inhibitors for Huntington’s disease [ 7 ]. In addition, 5-amino-1,2,4-oxadiazoles are used as a very promising energetic component for the preparation of high-energy-density materials (HEDMs) [ 8 , 9 ] (Fig.…”