Open Access4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds
Author(s) -
Muhammad Yasin,
Wardah Shahid,
Muhammad Ashraf,
Muhammad Saleem,
Saima Muzaffar,
- Aziz-Ur-Rehman,
Syeda Abida Ejaz,
Syeda Abida Ejaz,
Thomas Majer,
Keshab Bhattarai,
Naheed Riaz
Publication year - 2022
Publication title -
acs omega
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.779
H-Index - 40
ISSN - 2470-1343
DOI - 10.1021/acsomega.2c01439
Subject(s) - chemistry , triazole , arachidonate 5 lipoxygenase , ic50 , isoxazole , mtt assay , arachidonic acid , semicarbazide , stereochemistry , enzyme , in vitro , organic chemistry , biochemistry
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.