Vetting of new N-furfurylated p-chlorophenyl-1,2,4-triazole acetamides as lipoxygenase inhibitors assisted with in vitro and in silico studies

• Published in: Journal of the Iranian Chemical Society 2023-04, Vol.20 (4), p.977-994
• Main Authors: Riaz, Naheed, Yasin, Muhammad, Ashraf, Muhammad, Saleem, Muhammad, Bashir, Bushra, Iqbal, Ambar, Aziz-ur-Rehman, Ejaz, Syeda Abida, Ejaz, Samina, Mahmood, Hafiz Mohammad Kashif, Bhattarai, Keshab
• Format: Article
• Language: English
• Subjects: Analytical Chemistry; Biochemistry; Chemistry; Chemistry and Materials Science; Enzymes; Hydrogen bonding; In vitro methods and tests; Inorganic Chemistry; Ligands; Lipoxygenase; Liquid oxygen; Molecular docking; Organic Chemistry; Original Paper; Physical Chemistry; Proteins; Triazoles
• ISSN: 1735-207X; 1735-2428
• DOI: 10.1007/s13738-022-02733-2

Anti-inflammatory agents inhibit cyclooxygenase (COX) enzymes or lipoxygenase (LOX) enzymes to prevent inflammation implicated in various diseases including cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzymes but fewer drugs are marketed to inhibit the LOX enzymes. Therefore, the present work was aimed to synthesize N -alkyl/aralkyl/aryl derivatives ( 7a–p ) of 5-( p- chlorophenyl)- N -furfuryl-4H-1,2,4-triazol-3-ylthio)acetamide and screen them against 15-LOX by in vitro and in silico methods in search for leads. These compounds were produced by the sequential conversion of p -chlorobenzoic acid ( a ) into ester ( 1 ), hydrazide ( 2 ), 4-furfuryl-(1- p -chlorophenyl)thiosemicarbazide ( 3 ) and 5-( p -chlorophenyl)- N -furfuryl-4H-1,2,4-triazole-3-thiol ( 4 ) and finally 7a–p . These scaffolds ( 7a–p ) were characterized by modern techniques. Three analogues 7m , 7i, and 7o exhibited excellent inhibitory profiles with IC 50 values 19.59 ± 0.83, 24.52 ± 0.63 and 28.53 ± 0.76 µM, respectively, while others demonstrated good-to-moderate enzyme inhibitory activities (IC 50 34.32 ± 0.51 to 94.58 ± 0.74 µM). Compounds 7l , 7m , 7o , and 7n maintained cellular viability (%) 94.68 ± 1.3 to 71.46 ± 1.6 at 0.25 mM concentration, while 7k (57.74 ± 1.7%) and 7i (54.65 ± 1.5%) demonstrated cytotoxic potential in the MTT assay with mononuclear cells (MNCs). The molecular docking studies predicted that hydrophobic and van der Waal’s interactions predominantly stabilized the protein–ligand complexes, and hydrogen bonding was found operative only in 7e and 7a protein–ligand complexes. Compounds 7m , 7i, and 7o , presenting excellent inhibitory profiles, also displayed more stabilized LUMO energy profiles of − 0.057, − 0.056, and − 0.085 eV, respectively, in DFT calculations. Results collectively suggest that 7m , 7i , and 7o should further be investigated and derivatized in search for more potential leads as anti-LOX agents.