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Substituted aryl piperazine ligands as new dual 5-hLOX/COX-2 inhibitors. Synthesis, biological and computational studies
被引:0
作者:
Munoz-Osses, Michelle
[1
]
Navarrete, Elizabeth
[1
]
Morales, Pilar
[1
]
Quiroz, Javiera
[1
]
Silva, Maite
[2
]
Torres-Gonzalez, Simon
Vasquez-Martinez, Yesseny
[3
]
Godoy, Fernando
[2
]
Mascayano, Carolina
[1
]
机构:
[1] Univ Santiago Chile, Dept Ciencias Ambiente, Santiago, Chile
[2] Univ Santiago Chile, Dept Quim Mat, Santiago, Chile
[3] Univ Santiago Chile, Escuela Med, Fac Ciencias Med, Programa Ctr Invest Biomed & Aplicadas CIBAP, Santiago, Chile
关键词:
Aryl piperazine ligands;
5-hLOX;
COX-2;
Dual inhibitors;
Anti-inflammatory;
Computational studies;
ACTIVITY-RELATIONSHIP QSAR;
ARYLPIPERAZINE DERIVATIVES;
5-LIPOXYGENASE INHIBITION;
MOLECULAR-DYNAMICS;
CYCLOOXYGENASE;
DISCOVERY;
ZILEUTON;
DOCKING;
D O I:
10.1016/j.bioorg.2025.108398
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Two series of cyano (1a-l) and amino (2a-l) aryl piperazines were synthesized and evaluated for their inhibitory activity against 5-lipoxygenase (5-hLOX) and cyclooxygenase-2 (COX-2). The newly designed derivatives feature diphenyl methyl (a-d), phenyl (e-h), or methoxyphenyl (i-l) groups, respectively, and demonstrated significant inhibition of 5-hLOX. Noteworthy were compounds 1b, 1 g, 1 k, 2f, and 2 g, exhibiting IC50 values ranging from 2.2 to 3.3 mu M. The most potent inhibitors (1b, 1 g, 1 k, 2c, and 2f) were characterized by a competitive inhibition mechanism, with K-i values ranging between 1.77 mu M and 9.50 mu M. Additionally, compounds 2a, 2b, 2 g, and 2 h displayed promising dual inhibition of 5-hLOX and COX-2, with IC50 values below 15 mu M. Cytotoxicity assessments against HEK293 cells revealed that the cyano derivatives (1a-l) were non-cytotoxic (CC50 > 200 mu M), whereas the amino derivatives (2a-l) exhibited moderate cytotoxicity (CC50 < 50 mu M). Notably, the most active derivatives against both targets were non-cytotoxic at their respective inhibitory concentrations. Computational studies, including docking and molecular dynamics simulations, indicated that compound 1 g demonstrated greater stability within the catalytic site of 5-hLOX compared to compound 2f, correlating with the higher affinity observed in kinetic assays. Furthermore, quantitative structure-activity relationship (QSAR) analyses revealed strong correlations between theoretical and experimental IC50 values (97 % for 1a-l and 93 % for 2a-l). These findings, combined with absorption, distribution, metabolism, and excretion (ADME) predictions, suggest that these derivatives are promising candidates as dual inhibitors of 5-hLOX and COX-2.
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