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academies
J Pharmacol Ther Res 2017 Volume 1 Issue 2
November 02-03, 2017 Chicago, USA
4
th
International Congress on
International Conference and Exhibition on
Drug Discovery, Designing and Development
Biochemistry, Molecular Biology: R&D
&
Rational design of guanylthiourea derivatives as antimalarial agents
Shweta Bhagat, Prasad V Bharatam
and
Minhajul Arfeen
National Institute of Pharmaceutical Education and Research, India
P
lasmodium falciparum
dihydrofolate reductase (P
f
DHFR)
enzyme is one of the validated targets for antimalarial drug
discovery. The quadruple mutant of P
f
DHFR is resistant to the
known anti-P
f
DHFR drugs (e.g. proguanil, pyrimethamine and
trimethoprim). Recently, P218 was identified as a potential
lead molecule. In this work, a rational drug design strategy
was adopted to identify guanylthiourea (GTU) derivatives
as a potential P
f
DHFR inhibitor. Electronic structure analysis
of the GTU moiety was carried out to determine the correct
tautomeric formwhichwas 11.99 kcal/mol more stable than the
previously reported structure in the literature. Once acceptable
structure was established;
in silico
investigations on the wild
type/quadruple mutant P
f
DHFR and various ligands (including
MESP analysis, molecular docking studies) were performed to
design novel GTU derivatives as potential P
f
DHFR inhibitors.
Three series of GTU derivatives were synthesised, by reacting
bromides with GTU under reflux and microwave condition.
The synthesized compounds were first evaluated for
in vitro
P
f
DHFR inhibitory activity, resulting in the identification of
two compounds (100 µM and 0.4 µM). Further,
in vivo
studies
recognized six compounds with high mean survival time, out of
which one compound was identified to be curative. This work
reports a systematic rational approach for the structure-based
design of potential antimalarial agents.
e:
bhagatshweta61@gmail.com