Structure based drug design, synthesis and evaluation of 4-(benzyloxy)-1-phenylbut-2-yn-1-ol derivatives as 5-lipoxygenase inhibitors

A group of 4-(benzyloxy)-1-phenylbut-2-yn-1-ol derivatives were designed using Site point connection method, synthesized and evaluated for their 5-Lipoxygenase (5-LOX) inhibitory activity. Hydrophobic site points in 5-LOX were considered for the study and substitutions were planned such that 4k will have strong hydrophobic group in the corresponding site point. Biological results supported the in silico prediction with compound 4k exhibiting good inhibition with IC50 value of 8 μM against 5-LOX. The compounds 4j and 4k showed potent cytotoxic effects against various cancer cell lines (COLO-205, MDA-MB-231 and HepG2) but with no effect on normal cell line (HaCaT). The overall trend showed 4k as the most potent compound. Further studies demonstrated the protective effect of 4k in mouse Acute Lung Injury (ALI) model induced by lipopolysaccharide (LPS).

In this study, a group of 4-(benzyloxy)-1-phenylbut-2-yn-1-ol derivatives were designed using Site point connection method, synthesized and evaluated for their 5-Lipoxygenase (5-LOX) inhibitory activity.Figure optionsDownload as PowerPoint slideHighlights
► Single round lead optimization studies on 1-(benzyloxy) hept-2-yn-4-ol.
► Active site analysis and Site point connection methods were employed.
► A novel inhibitor of 5-LOX with an IC50 of 8 μM identified.
► The molecule identified showed potent anti-proliferative effects on cancer cells.
► Further studies demonstrated protective effects on LPS challenged mouse ALI.