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

Nimmanapalli P Reddy; T Chandramohan Reddy; Polamarasetty Aparoy; Chandrani Achari; P Ramu Sridhar; Pallu Reddanna

doi:10.1016/j.ejmech.2011.11.003

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

Eur J Med Chem. 2012 Jan;47(1):351-9. doi: 10.1016/j.ejmech.2011.11.003. Epub 2011 Nov 10.

Authors

Nimmanapalli P Reddy¹, T Chandramohan Reddy, Polamarasetty Aparoy, Chandrani Achari, P Ramu Sridhar, Pallu Reddanna

Affiliation

¹ School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India.

PMID: 22118829
DOI: 10.1016/j.ejmech.2011.11.003

Abstract

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 IC(50) 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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Lung Injury / chemically induced
Acute Lung Injury / pathology
Acute Lung Injury / prevention & control
Animals
Arachidonate 5-Lipoxygenase / chemistry
Arachidonate 5-Lipoxygenase / metabolism*
Benzyl Compounds / chemical synthesis
Benzyl Compounds / chemistry*
Benzyl Compounds / pharmacology*
Butanols / chemical synthesis
Butanols / chemistry*
Butanols / pharmacology*
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Humans
Inhibitory Concentration 50
Lipopolysaccharides / pharmacology
Lipoxygenase Inhibitors / chemical synthesis
Lipoxygenase Inhibitors / chemistry*
Lipoxygenase Inhibitors / pharmacology*
Mice
Models, Molecular
Structure-Activity Relationship

Substances

4-(benzyloxy)-1-phenylbut-2-yn-1-ol
Benzyl Compounds
Butanols
Lipopolysaccharides
Lipoxygenase Inhibitors
Arachidonate 5-Lipoxygenase