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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页数:12
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共 68 条
[1]   Licofelone - clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis [J].
Alvaro-Gracia, JM .
RHEUMATOLOGY, 2004, 43 :I21-I25
[2]   The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications [J].
Ayola-Serrano, Nohora Cristina ;
Roy, Namrata ;
Fathah, Zareena ;
Anwar, Mohammed Moustapha ;
Singh, Bivek ;
Ammar, Nour ;
Sah, Ranjit ;
Elba, Areej ;
Utt, Rawan Sobhi ;
Pecho-Silva, Samuel ;
Rodriguez-Morales, Alfonso J. ;
Dhama, Kuldeep ;
Quraishi, Sadeq .
INFLAMMATION RESEARCH, 2021, 70 (08) :877-889
[3]   MOLECULAR-DYNAMICS WITH COUPLING TO AN EXTERNAL BATH [J].
BERENDSEN, HJC ;
POSTMA, JPM ;
VANGUNSTEREN, WF ;
DINOLA, A ;
HAAK, JR .
JOURNAL OF CHEMICAL PHYSICS, 1984, 81 (08) :3684-3690
[4]   Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease [J].
Berger, W. ;
De Chandt, M. T. M. ;
Cairns, C. B. .
INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, 2007, 61 (04) :663-676
[5]   Synthesis, biological activities and docking studies of piperazine incorporated 1, 3, 4-oxadiazole derivatives [J].
Bhati, Shipra ;
Kumar, Vijay ;
Singh, Simranjeet ;
Singh, Joginder .
JOURNAL OF MOLECULAR STRUCTURE, 2019, 1191 :197-205
[6]   5-Lipoxygenase Antagonist therapy: a new approach towards targeted cancer chemotherapy [J].
Bishayee, Kausik ;
Khuda-Bukhsh, Anisur Rahman .
ACTA BIOCHIMICA ET BIOPHYSICA SINICA, 2013, 45 (09) :709-719
[7]   Synthesis, Evaluation of Enzyme Inhibition and Redox Properties of Potential Dual COX-2 and 5-LOX Inhibitors [J].
Boskovic, Jelena ;
Dobricic, Vladimir ;
Mihajlovic, Marija ;
Kotur-Stevuljevic, Jelena ;
Cudina, Olivera .
PHARMACEUTICALS, 2023, 16 (04)
[8]   Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma [J].
Bruno, Ferdinando ;
Spaziano, Giuseppe ;
Liparulo, Angela ;
Roviezzo, Fiorentina ;
Nabavi, Seyed Mohammed ;
Sureda, Antoni ;
Filosa, Rosanna ;
D'Agostino, Bruno .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 153 :65-72
[9]   Performance of Kier-hall E-state descriptors in quantitative structure activity relationship (QSAR) studies of multifunctional molecules [J].
Butina, D .
MOLECULES, 2004, 9 (12) :1004-1009
[10]   Development of quantitative structure activity relationship (QSAR) model for disinfection byproduct (DBP) research: A review of methods and resources [J].
Chen, Baiyang ;
Zhang, Tian ;
Bond, Tom ;
Gan, Yiqun .
JOURNAL OF HAZARDOUS MATERIALS, 2015, 299 :260-279