4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds

Abstract

Lipoxygenases (LOXs) are a class of enzymes that catalyze the production of pro-inflammatory mediators, such as leukotrienes and lipoxins, via an arachidonic acid cascade as soon as they are released from the membrane phospholipids after tissue injury. In continuation of our efforts in search for new LOX inhibitors, a series of chlorophenyl-furfuryl-based 1,2,4-triazole derivatives were prepared and evaluated for their 15-LOX inhibitory activities. A simple precursor, 4-chlorobenzoic acid ( a ), was consecutively transformed into benzoate ( 1 ), hydrazide ( 2 ), semicarbazide ( 3 ), and N -furfuryl 5-(4-chlorobenzyl)-4 H -1,2,4-triazole ( 4 ), which when further merged with electrophiles ( 6a–o ) resulted in end products ( 7a–o ). The structural elucidations of the newly synthesized compounds ( 7a–o ) were carried out by Fourier transform infrared, 1 H-, 13 C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. The inhibitive capability of compounds ( 7a–o ) on soybean 15-LOX was performed in vitro using the chemiluminescence method. The compounds 7k , 7o , 7m , 7b, and 7i demonstrated potent activities (IC 50 17.43 ± 0.38, 19.35 ± 0.71, 23.59 ± 0.68, 26.35 ± 0.62, and 27.53 ± 0.82 μM, respectively). These compounds revealed 79.5 to 98.8% cellular viability as measured by the MTT assay at 0.25 mM concentration. The structure-activity relationship (SAR) studies showed that the positions and the nature of substituents bonded to the phenyl ring are important in the determination of 15-LOX inhibitory activities. ADME, in silico, and density functional theory studies supported the evidence as yet another class of triazoles with potential lead properties in search for anti-LOX compounds with a safe gastrointestinal safety profile for various inflammatory diseases. Further work is in progress on the synthesis of more derivatives in search for anti-inflammatory agents.

Modular and Computational Access to Innocuous Multistep Metal-Free Synthesis of 1,3,4-Oxadiazoles as Enzyme Inhibitors

“…The presence of electron-donating or electron-withdrawing groups affects the HOMO–LUMO energy gap and changes the reactivity or interacting ability. Thus, the calculation of such energy gaps may inform about the inhibition potential of the synthesized compounds . The small HOMO–LUMO energy gap is characterized by high polarization, high reactivity, and low stability.…”

“…Thus, the calculation of such energy gaps may inform about the inhibition potential of the synthesized compounds. 23 The small HOMO–LUMO energy gap is characterized by high polarization, high reactivity, and low stability. Such molecules are termed soft ones.…”

Antiallergic Effects of Callerya atropurpurea Extract In Vitro and in an In Vivo Atopic Dermatitis Model

“…The 15-LOX inhibitory activity of Ca-EE was determined according to the method described by Yasin et al with a slight modification [ 66 ]. In addition, 15-LOXs promote the reaction between linoleic acid and oxygen, producing 13-hydroperoxyoctadecadienoic acid that can increase the absorbance at 234 nm.…”

Inhibitory Effects of Grewia tomentosa Juss. on IgE-Mediated Allergic Reaction and DNCB-Induced Atopic Dermatitis

“…The cell lysates were centrifuged at 12,000× g for 15 min at 4 °C to settle the cell debris and then stored at −70 °C until use. Protein concentrations were quantified using the Bradford assay (Bio-Rad, Hercules, CA, USA), and then immunoblotting analysis was carried out as previously described [ 79 ].…”

“…A total of 25 BALB/c mice (male, 5 weeks old) was randomly divided into 5 groups (PBS only, DNCB only, DNCB and Gt-EE 4 mg/kg, DNCB and Gt-EE 8 mg/kg, and DNCB and dexamethasone 8 mg/kg) [ 78 , 79 ]. DNCB, Gt-EE, and dexamethasone were all dissolved in PBS and applied directly to the ears of BALB/c mice.…”