Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum

Gowtham Subramanian; C P Babu Rajeev; Chakrabhavi Dhananjaya Mohan; Ameya Sinha; Trang T T Chu; Sebastian Anusha; Huang Ximei; Julian E Fuchs; Andreas Bender; Kanchugarakoppal S Rangappa; Rajesh Chandramohanadas; Basappa

doi:10.1016/j.bmcl.2016.05.049

Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum

Bioorg Med Chem Lett. 2016 Jul 15;26(14):3300-3306. doi: 10.1016/j.bmcl.2016.05.049. Epub 2016 May 18.

Affiliations

¹ Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore 487372, Singapore.
² Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
³ Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
⁴ School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
⁵ Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK; Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
⁶ Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK.
⁷ Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore 487372, Singapore. Electronic address: [email protected].
⁸ Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India. Electronic address: [email protected].

PMID: 27261180
DOI: 10.1016/j.bmcl.2016.05.049

Abstract

In this report, we describe the synthesis of 1-(Phthalazin-4-yl)-hydrazine using bronsted acidic ionic liquids and demonstrate their ability to inhibit asexual stage development of human malaria parasite, Plasmodium falciparum. Through computational studies, we short-listed chemical scaffolds with potential binding affinity to an essential parasite protein, dihydroorotate dehydrogenase (DHODH). Further, these compounds were synthesized in the lab and tested against P. falciparum. Several compounds from our library showed inhibitory activity at low micro-molar concentrations with minimal cytotoxic effects. These results indicate the potential of hydralazine derivatives as reference scaffolds to develop novel antimalarials.

Keywords: Antimalarials; Bronsted acidic ionic liquids; Dihydroorotate dehydrogenase; Hydralazines; P. falciparum.

Publication types

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

MeSH terms

Animals
Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Cell Line
Dogs
Dose-Response Relationship, Drug
Molecular Structure
Parasitic Sensitivity Tests
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Plasmodium falciparum / drug effects*
Structure-Activity Relationship

Substances

Antimalarials
Phthalazines