Parsing p-tolyloxy-1,3,4-oxadiazolepropanamides as 15-lipoxygenase inhibitors prop up by in vitro and in silico profiling including structure determination

Abstract

In humans, tissue injury result in the production of an inflammatory response and arachidonic acid released from the damaged membrane phospholipids is oxidized in two separate pathways, that is, lipoxygenase (LOX) and cyclooxygenase (COX) pathways, resulting in the production of biologically active mediators. The present work deals with the synthesis of a series of new N-alkyl/N-aryl derivatives (6a-n) of 5-((p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-ylthio)propanamide and these analogues (6a-n) were characterized by modern spectroscopic and spectrometric techniques and scanned for their inhibition for soybean 15-LOX enzyme. The results showed the derivatives 6g, 6i and 6j as potent enzyme inhibitors with an IC50 values 8.5 ± 0.4 µM, 11.4 ± 0.6 µM and 19.7 ± 0.4 µM. Compounds 6g and 6i maintained blood mononuclear cells (MNCs) viability of 75.5 ± 1.4%, 95.6 ± 1.5%, but 6j was found toxic with viability of 32.6 ± 1.6%, respectively, as determined by MTT assay. Rest of the compounds displayed good to poor inhibitory profiles against the said enzyme with IC50 values from 24.6 ± 0.6 µM to 83.5 ± 0.5 µM which were also found nontoxic to MNCs under assay conditions except 6k which revealed only 23.6 ± 1.3% cellular viability. Calculated ADME properties predicted ‘drug-like properties’ of all compounds with good oral bioavailability profiles. Molecular docking studies showed that Lys526 and Trp772 in 6g established hydrogen bonding with the protein and π-alkyl (Val126, Val520, Pro530) and alkyl interaction (Arg533) further helped the ligand protein binding as depicted in quercetin where hydrogen bonding and π-alkyl interaction was recognized. In summary, the derivatives 6g and 6i demonstrated highly appreciable drug-like properties and warrant further investigations in search for potential leads as anti-LOX agents.