Investigations of <i>p</i>-tolyloxy-1,3,4-oxadiazole propionamides as soybean 15-lipoxygenase inhibitors in comforting with <i>in vitro</i> and <i>in silico</i> studies
Creators: name: Bashir, Bushra
name: Riaz, Naheed
name: Ejaz, Syeda Abida
name: Saleem, Muhammad
name: Iqbal, Ambar
name: Ashraf, Muhammad
name: Ejaz, Samina
name: -Rehman, Aziz-ur
name: Aziz, Mubashir
name: Bhattarai, Keshab
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biophysics
subject: Biochemistry
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer

description: Inflammatory disorders are the prime contributor to public health issue and the development of more effective and safer anti-inflammatory drugs in addition to other therapeutic alternatives to treat inflammatory illnesses, particularly chronic inflammatory diseases, is one of the foremost current issues. In this regard, our present work is concerned with the synthesis of a new series of <i>N</i>-alkyl/aralkyl/aryl derivatives (<b>7a–o</b>) of 5-((<i>p</i>-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-ylthio)propionamide which was instigated by the successive conversions of <i>p</i>-tolyloxyacetic acid into ester, hydrazide and 5-(<i>p</i>-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol. The planned compounds (<b>7a–o</b>) were attained by the reaction of 5-(<i>p</i>-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol with variety of <i>N</i>-alkyl/aralkyl/aryl electrophiles in potassium hydroxide and were characterized by FTIR, <sup>1</sup>H-, <sup>13</sup>C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and probed for their inhibiting potential against soybean 15-lipoxygenase (15-LOX) enzyme. The compounds <b>7a, 7n, 7 g, 7e, 7h, 7i, 7j</b> and <b>7b</b> promulgated the potent inhibiting potential with IC<sub>50</sub> values 9.43 ± 0.45, 16.75 ± 0.49, 19.45 ± 0.37, 21.32 ± 0.46, 22.64 ± 0.56, 23.53 ± 0.62, 24.32 ± 0.45 and 29.15 ± 0.57 µM, respectively, while excellent to good inhibitory activities were shown by <b>7o, 7 m, 7k, 7f, 7c, 7 l</b> and <b>7d</b> with IC<sub>50</sub> values in the range 30.29 ± 0.56 to 52.54 ± 0.64 µM. Compounds <b>7i–o</b> maintained 91.12 ± 1.5 to 98.23 ± 1.2% blood mononuclear cells (MNCs) viability at 0.25 mM by MTT assay whilst compounds <b>7d–h</b> observed 46.51 ± 1.3 to 57.12 ± 1.4% viability where as the most toxic compounds were <b>7b</b> (12.51 ± 1.4%), <b>7a</b> (28.12 ± 1.5%) and <b>7c</b> (38.23 ± 1.5%) as compared with controls. Pharmacokinetic profiles predicted good oral bioavailability and drug-likeness properties of molecules as per rule of five. Molecular docking studies displayed hydrogen bonding between the compounds and the enzyme with Arg378 which was common in <b>7n</b>, <b>7 g</b>, <b>7h</b> and baicalein. In <b>7a</b> and quercetin, hydrogen bonding was established through Asn375; Tyr512 and Val589 were also involved in bonding with other analogues. RMSD (root mean square deviation) values exhibited good inhibitory profiles in the order quercetin (0.73 Å)&lt;<b>7 g</b> (0.98 Å)7a (1.27 Å)&lt;<b>7n</b> (1.75 Å)&lt;<b>7h</b> (1.81 Å) whereas the binding free energies (kJ/mol) increasing order: (−37.56 kJ/mol)&lt; quercetin (−35.43 kJ/mol)&lt;<b>7n</b> (−34.55 kJ/mol)&lt;<b>7 g</b> (−33.38 kJ/mol)&lt;<b>7h</b> (31.75 kJ/mol)&lt;<b>7a</b> (−31.63 kJ/mol). Density functional theory (DFT) data established good correlation between the IC<sub>50</sub> values of compounds and HOMO–LUMO (highest occupied and lowest unoccupied molecular orbitals) energy calculations. It was found that compounds with more stabilized LUMO orbitals had significant biological activity. The work collectively supports steps taken forward in search for potential ‘leads’ as anti-inflammatory agents wherein compounds <b>7a, 7n, 7i, 7j</b> possessed ‘lead’ like properties for further investigations. Communicated by Ramaswamy H. Sarma