A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2

Nirvanappa C Anilkumar; Mahalingam S Sundaram; Chakrabhavi Dhananjaya Mohan; Shobith Rangappa; Krishna C Bulusu; Julian E Fuchs; Kesturu S Girish; Andreas Bender; Basappa; Kanchugarakoppal S Rangappa

doi:10.1371/journal.pone.0131896

A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2

PLoS One. 2015 Jul 21;10(7):e0131896. doi: 10.1371/journal.pone.0131896. eCollection 2015.

Affiliations

¹ Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Palace Road, Bangalore-560 001, Karnataka, India.
² Department of Studies in Biochemistry, University of Mysore, Mysore-570 006, Karnataka, India.
³ Department of Studies in Chemistry, University of Mysore, Mysore-570 006, Karnataka, India.
⁴ Frontier Research Center for Post-genome Science and Technology Hokkaido University, Sapporo, 060-0808, Japan.
⁵ Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom.
⁶ Department of Studies in Biochemistry, University of Mysore, Mysore-570 006, Karnataka, India; Department of Studies and Research in Biochemistry, Tumkur University, Tumkur-572 103, Karnataka, India.

Abstract

Drugs such as necopidem, saripidem, alpidem, zolpidem, and olprinone contain nitrogen-containing bicyclic, condensed-imidazo[1,2-α]pyridines as bioactive scaffolds. In this work, we report a high-yield one pot synthesis of 1-(2-methyl-8-aryl-substitued-imidazo[1,2-α]pyridin-3-yl)ethan-1-onefor the first-time. Subsequently, we performed in silico mode-of-action analysis and predicted that the synthesized imidazopyridines targets Phospholipase A2 (PLA2). In vitro analysis confirmed the predicted target PLA2 for the novel imidazopyridine derivative1-(2-Methyl-8-naphthalen-1-yl-imidazo [1,2-α]pyridine-3-yl)-ethanone (compound 3f) showing significant inhibitory activity towards snake venom PLA2 with an IC50 value of 14.3 μM. Evidently, the molecular docking analysis suggested that imidazopyridine compound was able to bind to the active site of the PLA2 with strong affinity, whose affinity values are comparable to nimesulide. Furthermore, we estimated the potential for oral bioavailability by Lipinski's Rule of Five. Hence, it is concluded that the compound 3f could be a lead molecule against snake venom PLA2.

Publication types

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

MeSH terms

Animals
Daboia*
Group II Phospholipases A2 / antagonists & inhibitors*
Group II Phospholipases A2 / chemistry*
Molecular Docking Simulation*
Phospholipase A2 Inhibitors* / chemical synthesis
Phospholipase A2 Inhibitors* / chemistry
Pyridines* / chemical synthesis
Pyridines* / chemistry
Viper Venoms

Substances

Phospholipase A2 Inhibitors
Pyridines
Viper Venoms
Group II Phospholipases A2
VRV-PL-VIIIa phospholipase A2, Vipera russelli

Grants and funding

This research was supported by University Grants Commission (41-257-2012-SR), Vision Group Science and Technology, Department of Science and Technology (NO. SR/FT/LS-142/2012) to Basappa. KSR thanks DST-JSPS (DST/INT/JAP/P-79/09), DST Indo-Korea [INT/indo-korea/122/2011-12] and DST-PURSE for funding. AB thanks Unilever and the European Research Commission (ERC Starting Grant 2013) for funding. MSS thanks UGC-BSR for research fellowship and CDM thanks Department of Science and Technology for INSPIRE fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.