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Developing novel antimicrobial agents has become a necessitate due to the increasing rate of microbial resistance to antibiotics. All the newly adamantane derivatives were evaluated for their antimicrobial activities against six MDR clinical pathogenic isolates. The results exhibited that 13 compounds have from potent to good activity. Among those, five derivatives (6, 7, 9, 14a, and 14b) displayed the potent activities against the different isolates tested (MIC < 0.25 µg/ml with bacteria and <8 µg/ml with fungi) compared with Ciprofloxacin (CIP) and Fluconazole (FCA). Additionally, the potent adamantanes showed bactericidal and fungicidal effects based on (MBCs and MFCs) and the time‐kill assay. The most active adamantane derivatives 7 and 14b exhibited a synergistic effect of ΣFIC ≤ 0.5 with CIP and FCA against the bacterial and fungal isolates. Moreover, no antagonistic effect appeared for the tested derivatives. Additionally, the interaction of DNA gyrase and topoisomerase IV enzymes with the compounds 6, 7, 9, 14a, and 14b exhibited potent antimicrobial activity using in vitro biochemical assays and gel‐based DNA‐supercoiling inhibition method. The activity of DNA gyrase and topoisomerase IV enzymes showed inhibitory activity (IC50) of 6.20 µM and 9.40 µM with compound 7 and 10.14 µM and 13.28 µM with compound 14b, respectively. Surprisingly, exposing compound 7 to gamma irradiation sterilized and increased its activity. Finally, the in‐silico analysis predicted that the most active derivatives had good drug‐likeness and safe properties. Besides, molecular docking and quantum chemical studies revealed several important interactions inside the active sites and showed the structural features necessary for activity.

Foot-and-mouth disease (FMD) vaccine does not afford early effective protection until adaptive immune protection caused by the vaccination occurs. Therefore, an alternative prophylactic application of antiviral agents for inhibition of the FMD virus is needed, and this is the scope of this study. In this study, we tested nine adamantane-pyrazole derivatives that could exhibit antiviral activity against FMDV infection either in vitro through baby hamster kidney cells (BHK-21 cells) infected with FMD virus serotypes O pan Asia. Cytotoxicity Concentration 50 (CC 50) activity of pyrazole derivatives (1, 2, 3, 4, 5a,b, 6a-c) were detected on BHK-21 cells and ranged between 500 to 3000µg/ml. Inhibitory Concentration 50 (IC 50) on BHK-21 was achieved only for the most promising three derivatives 6a-c and exhibited an antiviral activity with a therapeutic index of 30, and that was reflected on the antiviral activity response in baby mice with different concentrations where a concentration of 50 µg/ml for pyrazole derivatives 6a and 6c compounds and 40 µg/ml for bis-tolyl pyrazole 6b that achieve 100% protection and this results was as effective as 50 µg/ml of amantadine. Specifically, diaryl pyrazole derivatives 6a-c that protected for six days following FMDV challenge. These results suggested that pyrazole derivatives 6a-c could be used as an effective antiviral agent against FMD virus infection. Molecular docking simulation of the target compounds 6a-c had good binding energy and the tested compounds recommended being an excellent 3C protease inhibitor compared to Amantadine and Ribavirin. These findings may explain the antiviral activity of the target compounds.