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.
Objective:
Conjugating quinolones with different bioactive pharmacophores to obtain potent anticancer
active agents.
Methods:
Fused pyrazolopyrimidoquinolines 3a-d, Schiff bases 5, 6a-e, two hybridized systems: pyrazolochromenquinoline
7 and pyrazolothiazolidinquinoline 8, different substituted thiazoloquinolines 13-15 and
thiazolo[3,2-a]pyridine derivatives 16a-c were synthesized. Their chemical structures were characterized
through spectral and elemental analysis, cytotoxic activity on five cancer cell lines, caspase-3 activation, tubulin
polymerization inhibition and cell cycle analysis were evaluated.
Results:
Four compounds 3b, 3d, 8 and 13 showed potent activity than doxorubicin on HCT116 and three compounds
3b, 3d and 8 on HEPG2. These promising derivatives showed increase in the level of caspase-3. The
trifloromethylphenyl derivatives of pyrazolopyrimidoquinolines 3b and 3d showed considerable tubulin polymerization
inhibitory activity. Both compounds arrested cell cycle at G2/M phase and induced apoptosis.
Conclusion:
Compounds 3b and 3d can be considered as promising anticancer active agents with 70% of colchicine
activity on tubulin polymerization inhibition and represent hopeful leads that deserve further investigation
and optimization.
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