Structure–Activity Relationship for the Oxadiazole Class of Antibacterials

Abstract

A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c showed potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.

π–π Noncovalent Interaction Involving 1,2,4- and 1,3,4-Oxadiazole Systems: The Combined Experimental, Theoretical, and Database Study

“…Among all the four oxadiazole types, 1,2,4- and 1,3,4-isomers are the most investigated for medicinal applications [ 23 ], and they are present in numerous marketed drugs, such as the Ataluren [ 25 ], Azilsartan [ 26 ], Opicapone [ 27 ], Naldemedine [ 28 ], and Raltegravir [ 29 ]. Moreover, many oxadiazole derivatives have been studied as antibiotics [ 30 , 31 , 32 , 33 , 34 ], fungicides [ 35 ], antivirals [ 36 ], anticancer [ 37 , 38 , 39 ], and anti-inflammatory [ 40 , 41 , 42 ] agents, neuroprotectors [ 43 , 44 , 45 ], as well as antidiabetic drugs [ 46 ] in recent years. This significantly stimulates further structural and theoretical studies on various noncovalent interactions involving oxadiazole-based compounds.…”

Synergism of a Novel 1,2,4-oxadiazole-containing Derivative with Oxacillin against Methicillin-Resistant Staphylococcus aureus

“…We report herein the synthesis and SAR results, against S. aureus, of a library of fifteen synthetic oxadiazoles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), featuring a common 5-(4 indolyl) substituent, and different aromatic substitutions at C-3 (Figure 1).…”

“…We report herein the synthesis and SAR results, against S. aureus, of a library of fifteen synthetic oxadiazoles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), featuring a common 5-(4′ indolyl) substituent, and different aromatic substitutions at C-3 (Figure 1). Starting from the lead structure 1 (Figure 2) discovered by Chang and coworkers [11], and featuring four interconnected aromatic rings named A-D, the same authors report an extensive structure-activity relationship that discloses compounds bearing a 5-indole ring A, for example, compound 2, (Figure 2), as the best candidates, in terms of activity, against Starting from the lead structure 1 (Figure 2) discovered by Chang and coworkers [11], and featuring four interconnected aromatic rings named A-D, the same authors report an extensive structure-activity relationship that discloses compounds bearing a 5-indole ring A, for example, compound 2, (Figure 2), as the best candidates, in terms of activity, against MSRA strains, low toxicity, oral bioavailability, and in vivo activity in murine models of infection [12][13][14].…”

“…The structure of the synthetized compounds was confirmed by analysis of the NMR data ( 1 H and 13 C NMR spectra) and ESI-MS (see Materials and Methods). Very recently, in the frame of our interest toward the development of 1,2,4-oxadiazolebased active molecules [15,16], we designed and synthesized a small library of oxadiazolecontaining compounds endowed with a polypharmacological profile against the enzymes of the eicosanoid biosynthesis [17].…”

“…New 1,2,4-oxadiazoles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were designed by fixing a common 4-indole ring at C-5, and by varying the aromatic substituent in position 3. These compounds were synthesized based on amidoxime and carboxylic acid heterocyclization and were tested for their antimicrobial activity against S. aureus 29213 and 43300 (MRSA), P. aeruginosa, and K. pneumoniae.…”