Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum.
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.
Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore 487372, Singapore.
Gowtham
G
Subramanian
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
C P
CP
Babu Rajeev
Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
Chakrabhavi Dhananjaya
CD
Mohan
Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore 487372, Singapore.
Ameya
A
Sinha
Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore 487372, Singapore.
Trang T T
TTT
Chu
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
Sebastian
S
Anusha
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Huang
H
Ximei
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.
Julian E
JE
Fuchs
Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK.
Andreas
A
Bender
Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
Kanchugarakoppal S
KS
Rangappa
Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore 487372, Singapore. Electronic address: rajesh@sutd.edu.sg.
Rajesh
R
Chandramohanadas
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India. Electronic address: salundibasappa@gmail.com.
Basappa
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D010793:Phthalazines
Antimalarials; Bronsted acidic ionic liquids; Dihydroorotate dehydrogenase; Hydralazines; P. falciparum