Synthesis, characterization and in vitro evaluation of novel enantiomerically-pure sulphonamide antimalarials.
Malaria parasites are currently gaining drug-resistance rapidly, across countries and continents. Hence, the discovery and development of novel chemical scaffolds, with superior antimalarial activity remain an important priority, for the developing world. Our report describes the development, characterization and evaluation of novel bepotastine-based sulphonamide antimalarials inhibiting asexual stage development of Plasmodium falciparum parasites in vitro. The screening results showed potent inhibitory activity of a number of novel sulphonamides against P. falciparum at low micromolar concentrations, in particular in late-stage parasite development. Based on computational studies we hypothesize N-myristoyltransferase as the target of the compounds developed here. Our results demonstrate the value of novel bepotastine-based sulphonamide compounds for targeting the asexual developmental stages of P. falciparum.
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India. salundibasappa@gmail.com.
Sebastian
S
Anusha
Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore. rajesh@sutd.edu.sg.
Ameya
A
Sinha
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India. salundibasappa@gmail.com.
C P
CP
Babu Rajeev
Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore. rajesh@sutd.edu.sg.
Trang T T
TT
Chu
Gulf Medical University, Ajman, United Arab Emirates.
Jessin
J
Mathai
School of Biological Sciences, Nanyang Technological University, Singapore.
Huang
H
Ximei
Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK and Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
Julian E
JE
Fuchs
Department of Studies in Chemistry, University of Mysore, Mysore, India.
NanjundaSwamy
N
Shivananju
Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
Andreas
A
Bender
School of Biological Sciences, Nanyang Technological University, Singapore.
Peter Rainer
PR
Preiser
Department of Studies in Chemistry, University of Mysore, Mysore, India.
Kanchugarakoppal S
KS
Rangappa
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India. salundibasappa@gmail.com.
Basappa
Pillar of Engineering Product Development, Singapore University of Technology & Design, Singapore. rajesh@sutd.edu.sg.
Rajesh
R
Chandramohanadas
D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000382:microbiology; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000962:Antimalarials; D010880:Piperidines; D011725:Pyridines; D013449:Sulfonamides; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; C108476:bepotastine