Exploration of the structure–activity relationship of 1,2,4-oxadiazole antibiotics

Abstract

We have recently disclosed the discovery of the class of 1,2,4-oxadiazole antibiotics, which emerged from in silico docking and scoring efforts. This class of antibacterials exhibits Gram-positive activity, particularly against Staphylococcus aureus. We define the structure-activity relationship (SAR) of this class of antibiotics with the synthesis and evaluation of a series of 59 derivatives with variations in the C ring or C and D rings. A total of 17 compounds showed activity against S. aureus. Four derivatives were evaluated against a panel of 16 Gram-positive strains, inclusive of several methicillin-resistant S. aureus strains. These compounds are broadly active against Gram-positive bacteria.

Three-dimensional QSAR analysis and design of new 1,2,4-oxadiazole antibacterials

“…The lead compound ( 1 , Figure 1A) was the basis for extensive structure-activity analysis. 17, 18 Here, we use the results of this effort to build a three-dimensional quantitative structure-activity relationship (3D-QSAR) model for these compounds in order to assist the design of novel analogues with improved activity.…”

Synthesis and Antibacterial Evaluation of 3,5-Diaryl-1,2,4-oxadiazole Derivatives

“…Synthesis of the 1,2,4-oxadiazol derivatives (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) Initially, the treatment of the nitrile derivatives with hydroxylamine hydrochloride produced the respective amidoximes in yields of about 98%, which reacted with the carboxylic acid chlorides yielding the 1,2,4-oxadiazole nuclei (Scheme 1).…”

“…The compounds were synthesized based on the structural skeleton reported in Table 1, 25,26,39 which has the central 1,2,4-oxadiazole nucleus and phenyl radicals linked at the C-3 and C-5 positions of the heterocycle. Thus, two sets of compounds involving chlorinated and pyridine derivatives were synthesized.…”

“…The medium was refluxed for 2 h. Only acyl chloride (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) remained in the flask after the excess thionyl chloride was removed by distillation. 20 Synthesis of the 1,2,4-oxadiazol derivatives (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) The newly synthesized acyl chloride dissolved in toluene (10 mL) was slowly added to a solution of amidoxime (2.5 mmol) dissolved in toluene (40 mL) in a 250 mL round-bottomed flask at 25 o C and under constant stirring. After the addition, the solution was refluxed for 20 h, and then washed with sodium carbonate solution.…”

The oxadiazole antibacterials

“…Replacing the bridging oxygen with a sulfide or an amine did not affect the antibacterial activity. Fused C and D rings were mostly inactive or had a higher MIC values of 8 μg/mL [22]. Replacing the trifluoromethyl at the 4-position of the diphenyl ether moiety with a fluorine (antibacterial 4 ) did not affect activity.…”