Journal
BIOORGANIC CHEMISTRY
Volume 129, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.106144
Keywords
Lipoxygenase inhibition; Computational studies; MTT assay; ADME studies; Tolyloxyoxadiazole acetamides; Synthesis Characterization
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The correlation between inflammation, innate immunity, and cancer has been extensively studied, and researchers are now focusing on synthesizing new molecules with safer profiles to overcome the reported side effects and resistance of anti-inflammatory drugs. This study investigated the synthesis of a new series of 1,3,4-oxadiazole derivatives and evaluated their inhibitory potential against the soybean 15-LOX enzyme. The results showed excellent inhibitory activity of some compounds, as well as their low cellular viability in blood mononuclear cells.
The underlying correlation between the inflammation, innate immunity and cancer is extensively familiar and linked through a process mediated by three enzymes; cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). The ever increase in the reported side effects of the antiinflammatory drugs against the targeted enzymes and the resistance developed afterwards compels the researchers to synthesize new effective molecules with safer profile. On the basis of these facts, our ongoing research on 1,3,4-oxadiazole derivatives deals with the synthesis of a new series of N-alkyl/aralky/aryl derivatives of 5-((p-tolyloxymethyl)-4H-1,3,4oxadiazole-2-ylthio)acetamide (6a-o) which were developed by the sequential conversion of p-tolyloxyacetic acid (a) into ester (1) hydrazide (2) and 5-(p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol (3). The designed compounds (6a-o) were acquired by the reaction of 1,3,4-oxadiazole (3) with numerous electrophiles (5a-o) in KOH. The synthesized analogues (6a-o) were characterized by FTIR, 1H-, 13C NMR spectroscopy, EI-MS and HREI-MS spectrometry, and were further assessed for their inhibitory potential against the soybean 15-LOX enzyme. The results showed excellent inhibitory potential of the compounds against the said enzyme, specifically 6o, 6b, 6n and 6e with inhibitory values (IC50 +/- SEM) of 21.5 +/- 0.76, 24.3 +/- 0.45, 29.1 +/- 0.65 and 31.3 +/- 0.78 mu M, respectively. These compounds displayed < 55 % blood mononuclear cells (MNCs) cellular viability as measured by MTT assay at 0.25 mM concentration. Other compounds demonstrated moderate inhibitory activities with IC50 values in the range of 33.2 +/- 0.78 to 96.3 +/- 0.73 mu M and exhibited little cellular viability against MNCs except 6i, 6j, 6 m and 6 k that showed 61-79 % cellular viability. It was observed that most of the compounds (6o, 6b, 6n, 6e) were found more toxic towards MNCs at studied concentration of 0.25 mM. SAR studies revealed that the positions and nature of substituents accompanying phenyl ring have great influence on 15-LOX inhibitory activity. In the most active compound 6o, the amino acids Asp768 and Val126 were involved in hydrogen bonding, Thr529 was linked with p-anion interaction and p-sulphur interaction was displayed with Tyr525 and two p-alkyl interactions were formed with the benzene ring and amino acid residues Pro530 and Arg533. The in silico pharmacokinetics profiles and density functional theory calculations of the compounds further supported the in vitro findings. Further work on the synthesis of more oxadiazole derivatives is in progress in search for potential `leads' for the drug discovery as LOX inhibitors.
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