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.com
Volume 4, Issue 4 (Suppl)
J Pharma Care Health Sys
ISSN: 2376-0419, JPCHS, an open access journal
Pharma Middle East 2017
September 25-26, 2017
September 25-26, 2017 Dubai, UAE
12
th
Annual Pharma Middle East Congress
Pharmacophore guided design, synthesis and biological evaluation of novel HDAC8 inhibitors with
antitumor potential
Manal Mohammed and M J N Chandrasekar
JSS College of Pharmacy, India
E
pigenetic regulation of gene expression is explicitly controlled via chromatin remodeling, which in turn is controlled
through Post-Translational Modifications (PTM) of histone tails. The known PTMs include acetylation, methylation,
phosphorylation, sumoylation and ubiquitylation. In neoplasms, themechanismof histone acetylation gets imbalanced through
the overexpression of Histone Deacetylase (HDAC) and/or inactivation of Histone Acetyl Transferase (HAT). Moreover, it
extends to a plethora of effects including aberrant gene expression, oncogene activation, tumor suppressor gene inactivation
and tumor progression. HDAC inhibitors regulate the gene expression and display anticancer potential. In the present study, a
pharmacoinformatic approach was applied to develop a pharmacophore model based on a data set of 42 N-(2-aminophenyl)
benzamide analogues reported for HDAC inhibitory profile. The generated model comprised of six chemical points, namely
two hydrogen bond donors, two hydrogen bond acceptors and two aromatic rings. The statistically validated model (R
2
, SD,
RCV
2
, etc.) was further employed as a basis to design a library of 138 leads, which was checked for matching fitness against the
model. The final hits were selected for chemical synthesis depending on binding interaction(s) after molecular docking, binding
free energies and
in silico
ADME properties. These synthesized hits, containing oxadiazole and thiadiazole heterocycles, were
investigated for their
in vitro
HDAC8 inhibitory and antitumor activity. Among all the compounds, the hydroxamic acid
analogue containing p-tolyl substituted thiadiazole displayed better HDAC8 inhibitory potential and significant anticancer
activity in comparison to FDA approved HDAC inhibitor, SAHA. These results warrant further investigations to substantiate
the compound as a promising drug for the treatment of cancer.
Biography
Manal Mohammed is currently pursuing her PhD in Pharmaceutical Chemistry at JSS University, India. Her PhD work focuses on the design and synthesis of novel
compounds as histone deacetylase (HDAC) inhibitors for cancer therapy. Her research interests include molecular modeling and
in silico
design of novel molecules
using computational tools.
manal_mohd@rediffmail.comManal Mohammed et al., J Pharma Care Health Sys 2017, 4:4 (Suppl)
DOI: 10.4172/2376-0419-C1-023