Novel thiazole–oxadiazole hybrid compounds: In vitro antimicrobial testing, molecular modeling, and pharmacokinetic profiling

Three novel series of thiazole-oxadiazole hybrid compounds, 5a-c, 7a-c, and 9a-c , were synthesized and characterized by IR, NMR, and MS analyses. Optimizing the produced conjugates via the denisity function theory (DFT/B3LYP) method released planar configurations, except for acetyl oxadiazoles 9a-c . The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of 5a-b and 7a-b analogues were overlaid mainly on the thorough scaffold, while those belonging to 9a-b were excluded from the oxadiazolyl substituent phenyl ring. In contrast, the frontier molecular orbital (FMO) of nitrophenyl analogues ( 5c, 7c, and 9c ) was confined to the thiazolyl-phenylamino-oxadiazole and oxadiazolyl nitrophenyl portions, respectively. Moreover, the studied hybrids demonstrated diverse and potent antimicrobial activities. For instance, hybrid 7b had a broader and more effective spectrum than the reference antibiotics, with an minimum inhibitory concentration (MIC) value of 3.125 µg/mL and IZ = 26 mm. In addition, the bacterial DNA gyrase inhibitory effect of the investigated series was evaluated, and several hybrids demonstrated significant activity, especially hybrids 7b, 7c, and 9c (IC 50 = 4.28 ± 0.54–4.55 ± 0.23 µM), which closely matched the reactivity of novobiocin (reference). A docking study of the bacterial DNA gyrase B receptor (PDB ID: 6YD9) was performed to investigate its interactions with the synthesized conjugates, where hybrids 7b and 7c exhibited the most promising scores. Moreover, pharmacokinetic evaluation revealed high gastrointestinal absorption with no predicted P-glycoprotein (P-gp) substrate activity.