European Journal of Medicinal Chemistry 164 (2019) 214e240

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to

other isoforms: An overview
Suvankar Banerjee, Nilanjan Adhikari 1, Sk Abdul Amin, Tarun Jha*
Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur
University, Kolkata, 700032, West Bengal, India

a r t i c l e i n f o a b s t r a c t

Article history: The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells
Received 22 September 2018 through deacetylation of nuclear histone proteins. Discoveries related to the HDAC8 enzyme activity
Received in revised form signified the importance of HDAC8 isoform in cell proliferation, tumorigenesis, cancer, neuronal disor-
4 December 2018
ders, parasitic/viral infections and other epigenetic regulations. The pan-HDAC inhibitors can confront
Accepted 16 December 2018
Available online 19 December 2018
these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of
selective HDAC8 inhibitors is a key feature to combat the pathophysiological and diseased conditions
involving the HDAC8 activity. This review is concerned about the structural and positional aspects of
Keywords:
Histone deacetylase
HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiological condi-
HDAC8 tions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to
Cancer deliver the structural, functional and computational information in order to identify and design potent
HDAC8 inhibitor and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymatic
Structure-activity relationship (SAR) activity.
Quantitative structure-activity relationship © 2018 Elsevier Masson SAS. All rights reserved.
(QSAR)

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
2. A short trip to HDAC enzymes and its classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
3. FDA approved HDAC inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
3.1. Vorinostat (suberoylanilide hydroxamic acid/SAHA/Zolinza®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
3.2. Romidepsin (Istodax®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
3.3. Belinostat (Beleodaq®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
3.4. Panobinostat (Farydak®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
3.5. Pracinostat (SB939) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
3.6. Chidamide (HBI-8000/Epidaza®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
4. Role of HDAC8 in different diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
5. Structure of HDAC8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
6. An insight into the HDAC8 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
7. QSAR studies on HDAC8 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
8. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

* Corresponding author.
E-mail address: tjupharm@yahoo.com (T. Jha).
1
Present Address: School of Pharmaceutical Technology, ADAMAS University, Barasat-Barrackpore Road, P. O. Jagannathpur, Kolkata e 700126, West Bengal, India.

https://doi.org/10.1016/j.ejmech.2018.12.039
0223-5234/© 2018 Elsevier Masson SAS. All rights reserved.
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
1. Introduction
Histone deacetylases (HDACs), called as eraser enzymes, belong
to the class of Zn2þ or nicotinamide adenine dinucleotide (NADþ)-
dependent proteolytic enzymes. These HDACs are involved in the
transcriptional repression and chromatin condensation mecha-
nisms by removing the acetate moiety form acetylated 3-amino
groups of histone lysine and other non-histone protein [1e3]. This
process of deletion of the acetate group from the acetylated
3 -amino lysine of histone proteins is known as “deacetylation of
histone proteins” (Fig. 1). Hence, the HDAC enzymes are also known
as “Lysin Deacetylase” (KDAC) enzymes [3].
Due to the deacetylation property, HDACs participate in a
number of important biological signaling pathways through regu-
lation and modulation of these pathways [4]. The enzymatic ac-
tivities of HDAC isoforms are responsible for maintenance of several
normal physiological conditions. These HDAC isoforms are also
involved in the occurrence and progression of a number of patho-
physiological conditions and diseases. These include neurodegen-
erative disorders, cancers, inflammation, autoimmune diseases and
metabolic disfunctions [4]. For contributions of the HDAC enzymes
in the pathophysiological conditions, these HDAC enzymes have
became an interesting and important target to combat the diseased
conditions and especially cancers and tumors [5,6]. The interrup-
tion in the normal expression of HDAC enzymes or their activity
causes abnormal cellular functionality lead to generation of mul-
tiple diseased conditions [4]. The abnormal HDAC expression and
their abnormal deacetylation activity became a very popular and
interesting topic for the prevention of the pathophysiological
conditions including cancer generation and progression [1,4,7,8].
HDAC enzymes are categorized into two groups: the Zn2þ-depen-
dent HDACs [namely class I (HDAC1, 2, 3 and 8), class II (HDAC4, 5, 6,
7, 9 and 10) and class IV (HDAC11)] and the nicotinamide adenine
dinucleotide (NADþ)-dependent enzymes [class III sirtuins]. More
than 15 year ago, HDAC8 was discovered as a Zn2þ dependant class
Ic HDAC enzyme which has a size of 42 kDa comprising 377 amino
acids [1,4,9,10]. Among the diverse class of HDACs, HDAC8 can be
identified easily from the other HDAC enzymes of the class due to
its unique structural and functional specializations compared to the
other HDAC isoforms of the class [1,4]. The X-linked structure of
human HDAC8 and its co-factor independent activity is dissimilar
Fig. 1. Deacetylation of lysine residue of histone proteins by histone deacetylase 8 (HDAC8) along with inhibition of HDAC8 by HDAC8 inhibitor.
215
to the other HDAC isoforms of the class. Additionally, the C-ter-
minal protein binding domain of other HDACs is found to be absent
in HDAC8 [4]. Moreover, the attachment of some non-histone
proteins like cohesin, cortactin, Estrogen Related Receptor a
(ERRa) with HDAC8 has been observed [1,4]. Beside the arguable
fact about the histone proteins as the major or actual target of
HDAC8 enzyme, there are a number of non-histone proteins (such
as SMC3, EPR-a and p53) those have been reported as important
factors of HDAC8 deacetylation [11,12]. The importance of HDAC8
enzyme activity for the expression of both wild type and mutated
p53 has also been observed [13]. The knockdown of HDAC8 resulted
in the antiproliferative activity for the cells carrying a p53 mutant,
but the same results have not been seen for the cells with wild type
p53 indicating that HDAC8 inhibition can serve well for tumors
containing mutant p53 as an adjuvant therapy [4,7]. Though the
important role of HDAC8 in the patterning of mice skull cranial
neural creast cell and skull stability have been seen, the expression
of HDAC8 has been seen in colon, lung and pancreatic cancers,
acute lymphocytic leukemia (ALL) and acute myeloid leukemia
(AML) including childhood neuroblastoma [4,14,15]. The knock-
down of HDAC8 gene through the RNAi mediated process proved
the essentiality of HDAC8 enzyme for proliferation in human colon,
lung and cervical cancers, gastric adeno carcinoma and leukemia
[4]. The role of HDAC8 in both sistosomasis and viral infections was
reported. The abnormal enzymatic activity of HDAC8 isoform has
also been reported in Cornelia de Lange Syndrome (CdLS) [16,17].
HDACs also affect the gelatinase enzymes (MMP-2, MMP-9) in
cancer progration. HDAC enzyme causes up regulation of the
gelatinase enzymes leading to the tumor progression and metas-
tasis [1e3]. The inhibition of HDAC enzymes including HDAC8
causes inhibition of the deacetylation activity of HDAC8 enzyme
and induces acetylation of the histone and non-histone proteins.
This inhibition leads to restrict the DNA repairing, cell cycle arrest,
alteration in genetic expression and induces cellular apoptosis [2].
From studies on HDAC inhibitors, it has been seen that most of the
HDAC inhibitors including the HDAC8 inhibitors contains three
pharmacophoric features in its scaffold known as the Zinc binding
group (ZBG), CAP region and a linker moiety presents between the
CAP and ZBG [1e3]. It has been seen that the ZBG causes cheletion
with the HDAC8 Zn2þ ion where the hydrophobic CAP region fits
and interacts with the HDAC8 pocket whereas the linker helps to
216 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
maintain the distance between the ZBG and the CAP region while
binding [1e3]. The linker region also interacts with the amino acid
residues of the HDAC8 catalytic domain [18]. Till date, only five
HDAC inhibitors namely, Vorinostat (SAHA/Zolinza®), Romidepsin
(Istodax®), Panobinostat (Farydak®), Belinostat (Beleodaq®) and
Pracinostat (SB939) have been approved by USFDA (United States
Food and Drug Administration) and one HDAC inhibitor namely
Chidamide (HBI-8000/Epidaza®) is approved by Food and Drug
Administration, China for the treatment of peripheral T-cell lym-
phoma (PTCL) [3]. However, these HDAC inhibitors are pan-HDAC
inhibitors. These interact with all classes of HDACs and lead to
adverse effects. Therefore, isoform-specific HDAC8 inhibitors are
important.
2. A short trip to HDAC enzymes and its classification
The group of HDAC contains a number of isoforms in its family. A
total of 18 HDAC isoforms belong to the group comprising either
Zn2þ or NADþ in their structures [8]. On the basis of their structural,
functional as well as origin, HDACs are categorized into four
different classes. Among these four classes of HDACs, the class I and
class II isoforms exhibit structural similarity with the yeast RPD3
deacetylase and yeast Hda I enzymes respectively [4,12,19]. The 11
HDACs belongs to class I, II and IV are Zn2þ-dependent metal-
loenzymes whereas the class III HDACs (known as sirtuins/SIRTs)
are NADþ-dependent with 7 members (SIRT 1-7) [2,9,20]. The class
IV HDAC family contains only HDAC11 (Table 1) which differs from
the other three classes of HDACs. The structural difference is due to
its sequence with other class of HDACs. However, the catalytic re-
gion resembles for both class I and class II HDACs [10,12].
The major class of HDACs (class I and class II) are known as the
classical HDACs. These possess the conserved deacetylase core
domain which is responsible for the elimination of N-terminal
acetyl group from the lysine residues in presence of Zn2þ ion [21].
The isoforms of class I HDACs can be further subdivided into three
subclasses namely class IA (HDAC1, HDAC2), class IB (HDAC3) and
class IC (HDAC8) depending on their phylogenic data. HDAC8 is
being regulated by protein kinase A (PKA) whereas casein kinase-2
is responsible for the regulation of class IA isoforms (HDAC1,
HDAC2) [4]. The class I HDACs are responsible for the catalysis of a
wide range of non-histone and histone substrates including a va-
riety of transcriptional factors [12]. Similarly, the class II HDACs
(HDAC4, HDAC5, HDAC6, HDAC7, HDAC10) can also be classified
into two subclasses such as class IIA (HDAC4, HDAC5, HDAC7) and
class IIB (HDAC6, HDAC9, HDAC10) [1e3,10,12]. The class I HDACs
localizes into the neucleoplasm of cells whereas the class II and
class IV HDACs are found in both cytoplasm and nucleus (Fig. 2).
Interestingly, the SIRTs are also localized into the mitochondria.
HDAC6 is the only enzyme of class II HDAC family which is mostly
Table 1
Classification of HDACs (listed below are the cellular location, non-histone substrates and complexes HDACs).
Class Dependency Sub class Isoform Cellular localization
I Zn2þ IA HDAC1 Nucleus
HDAC2 Nucleus
IB HDAC3 Nucleus
IC HDAC8 Nucleus
II IIA HDAC4 Nucleus/Cytoplasm
HDAC5 Nucleus/Cytoplasm
HDAC7 Nucleus/Cytoplasm
IIB HDAC6 Mostly Cytoplasm
HDAC9 Nucleus/Cytoplasm
HDAC10 Nucleus/Cytoplasm
III NADþ e SIRTs Nucleus/Cytoplasm/Mitochondria
IV Zn2þ e HDAC11 Nucleus/Cytoplasm
localized into the cytoplasm [10]. The conserved serine residue
incorporated into the class IIA isoforms that is responsible for
phosphorylation [1]. The HDAC10 is composed of an active deace-
tylase domain along with an incomplete domain while the HDAC6
comprises two catalytic domains along with a carboxyl terminus
zinc figure motif [1,2].
3. FDA approved HDAC inhibitors
During the long era to discover an effective HDAC inhibitor for
prevention of HDAC enzymes which contribute in development
and progression of cancer, a number of ligands have been synthe-
sized with HDAC inhibitory activity [22e26]. Unfortunately, only a
handful of inhibitors among them provided promising results.
Some of the promising molecules have been tested and are evalu-
ated in the different phases of clinical trials. However, only six
HDAC inhibitors (HDACIs) have successfully passed the clinical trial
studies till now (Fig. 3) and proved themselves to combat cancer. 5
out of 6 approved HDAC inhibitors have been approved by the
USFDA (United States Food and Drug Administration).
3.1. Vorinostat (suberoylanilide hydroxamic acid/SAHA/Zolinza®)
Vorinostat (suberoylanilide hydroxamic acid/SAHA, FDA-01) is a
potent and orally active HDAC inhibitor. It shows activity against all
the HDAC enzymes (Table 2, Fig. 3) including HDAC8 (HDAC8
IC50 ¼ 1480 nM) [1,2,25]. For haematological malignancies such as
cutaneous T-cell lymphoma (CTCL) and solid tumors, responses
were noted for SAHA [27]. A maximum of 400 mg of SAHA can be
tolerated orally for haematological cancers. However, for solid tu-
mors, a maximum of 600 mg can be tolerated [28]. Not only that,
SAHA was found to be an effective radiosensitizer in human glio-
blastoma in preclinical studies [29].
SAHA effectively exhibited a potent antiproliferative and
apoptotic activity in type I and type II human endometrial cancers
by modulating the expressions of some genes related to specific
Insulin-like growth factor-I (IGF-I) receptor signaling pathway [30].
SAHA enhanced the phosphorylation of IGF-IR, upregulated the
expression of PTEN and p21 as well as reduced the levels of cyclin
D1 and p53 in the type I human endometrial cancer cell lines
whereas caused the upregulation of IGF-IR, expression of p21 and
downregulation of cyclin D1, total AKT and PTEN expressions when
evaluated in the type II human endometrial cancer cell lines.
Fascinatingly, SAHA was also found to hyperacetylate the histone
H3 in the type I and II endometrial cancers [31,32]. In murine and
human lung cancer cell lines along with the genetically engineered
lung cancer models in mouse, SAHA profoundly decreased cancer
cell proliferation along with expressions of cyclin D1 and cyclin E
but increased the expression of p27, apoptosis and histone
Non-histone substrates Complex
SHP,p53,MyoD,E2F1, STAT3, NF-kB,CtIP,AMPK, RB1 Sin3, NURD
GCCR,BCL6,STAT3, YY1 Sin3, NURD
SHP, YY1, GATA1, p65, STAT3, MEF2D NCOR1/NCOR2-GPS2-TBL1X
SMC3, actin ____
GATA1, HP1 NCOR1/NCOR2
SMAD7, HP1 ____
PLAG1, PLAG2 Sin3, NCOR2
a-tubulin, HSP90, SHP, SMAD ____
____ ____
____ NCOR2
Not given Not given
____ ____
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Fig. 2. Schematic representation of histone deacetylase (HDAC) super family members.
acetylation [33]. Radiosensitization by SAHA along with capecita-
bine under hypoxia reduced in vitro colonogenicity and inhibited
in vivo tumor growth in colorectal carcinoma xenograft models
[34]. However, SAHA in combination with CHOP (cyclophospha-
mide, doxorubicin, vincristine and prednisone) exhibited weak
prognosis in the clinical trials while treating patients having un-
treated peripheral T-cell lumphoma (PTCL) [35]. SAHA was also
found to be a potent anticancer agent effective against gastroin-
testinal cancer [36]. It was interesting to note that SAHA basically
acts as a pan-HDAC inhibitor due to inhibition of all HDACs (class I,
II and IV HDAC) but not the NADþ-dependent sirtuins or class III
HDACs [19,37].
3.2. Romidepsin (Istodax®)
Romidepsin (FDA-02) (Table 2, Fig. 3), reported in 1994 in the
scientific literature performed by a group of researchers from
Fujisawa Pharmaceutical Company in Tsukuba of Japan. It was
isolated from Chromobacterium violaceum culture obtained from a
soil sample [38]. In the phase I clinical study, the maximum toler-
ated dose (MTD) of romidepsin was identified when carried out on
217
37 patients having various type of tumors [10]. The FDA approval
for romidepsin in the treatment of relapsed or refractory peripheral
T-cell lymphomas (PTCL) was mainly established from the data
obtained from the pivotal GPI-06-0002 trial. In the trial of 131
patients with relapsed or refractory PTCL, the treatment with
romidepsin provided better beneficial results [39].
3.3. Belinostat (Beleodaq®)
Belinostat (FDA-03) is a HDAC inhibitor comprising a
sulphonamide-based hydroxamate structure. It is chemically (2E)-
N-hydroxy-3-[3-(phenylsulfamoyl)-phenyl]-prop-2-enamide
which was primarily metabolized by the enzyme UGT1A1 and to
some extent by CYP2A6, CYP2C9 and CYP3A4 as observed in the
in vitro studies (Table 2, Fig. 3). The in vitro studies revealed that
Belinostat also inhibited the enzymatic activity of HDAC8
(IC50 ¼ 3530 nM) along with CYP2C8 and CYP2C9 [26,40].
3.4. Panobinostat (Farydak®)
Panobinostat (FDA-04), another hydroxamate HDAC inhibitor,
218 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240

Fig. 3. Structures of FDA approved HDAC inhibitors (FDA-01 e FDA-06).

Table 2
Histone deacetylase inhibitors (HDACIs) approved by the FDA for the treatment of cancer.

Sl No. HDAC inhibitor Therapeutic use Trade name Company name Year of approval Reference

(FDA-01) Vorinostat (SAHA) Cutaneous T-cell lymphoma Zolinza Merck 2006 [27,28]
(FDA-02) Romidepsin Cutaneous T-cell lymphoma Istodax Celgene 2009 [10,38]
(FDA-03) Belinostat Relapsed multiple myeloma Beleidaq Spectrum 2014 [40]
(FDA-04) Panobinostat Relapsed multiple myeloma Farydak Novartis 2015 [10]
(FDA-05) Chidamide (HBI-8000) Relapsed or refractory peripheral T-cell Epidaza Shenzhen-core biotechnology limited 2015 [41]
lymphoma and pancreatic cancer
(FDA-06) Pracinostat (SB939) Acute myeloid leukemia ____ Helsinn Group and MEI Pharma 2016 [42]

acts as a non-selective pan HDAC inhibitor (Table 2, Fig. 3). It was
approved by USFDA for the treatment of multiple myolema [1,10]. It
also exhibited activity against haematological and solid cancers in
phase II clinical trial [10].
3.5. Pracinostat (SB939)
Pracinostat (FDA-05) was found to inhibit class I, II, IV HDACs
without inhibiting class III HDACs and HDAC6. It had no effect on
other zinc dependent enzymes (Table 2, Fig. 3). It accumulated into
the tumor cells and subsequently exhibited histone deacetylase
inhibition followed by acetylation of histones, remodelling of
chromatin, transcription of tumor suppressor genes as well as
apoptosis in tumor cells [41]. Pracinostat exhibited promising
in vitro activity against HDAC8 isoform (HDAC8 IC50 ¼ 140 nM) [42].
3.6. Chidamide (HBI-8000/Epidaza®)
Chidamide is the only HDAC inhibitor approved by Chinese Food
and Drug Administration (CFDA) unlike other approved HDAC in-
hibitors which are approved by USFDA [43].
It is important to note that all these FDA approved drugs are
nonselective pan-HDAC inhibitors those possess a number of
adverse effects and therefore, their use is limited to particular type
of cancers. However, HDAC8 has a direct relation in progression of
several types of cancers. Therefore, specific and selective HDAC8
inhibitors may be effective to combat these particular cancers with
lower adverse effects. Moreover exept these six approved HDAC
inhibitors (FDA01-FDA06), a number of promising ligands such as
Givinostat, Tacedinaline, Entinostat, Resminostat, etc. [10] also have
entered into the preclinical and clinical studies. These compounds
bear a possibility to become an important weapon in combating
various cancers and designing newer molecules through modifi-
cation of these compounds may provide excellent HDAC8
inhibition.

Chidamide (FDA-06), a benzamide derived HDAC inhibitor, is 4. Role of HDAC8 in different diseases
also known as HBI-8000 that inhibits class I HDACs (HDAC1,
HDAC2, HDAC3 and HDAC8) as well as Class IIb HDAC (HDAC10). It The overexpression of HDAC8 has been observed in a variety of
is being used for the treatment of pancreatic cancer (Table 2, Fig. 3). cancers (colon, lung, breast, pancreatic cancers and neuroblastoma
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
in childhood cancer) (Fig. 4).
The level of HDAC8 expression is almost identical in cancer cells
and in healthy tissues with a tendency to increase its expression in
cancer cells [15,44]. The RNA interference (RNAi) mediated
knockdown of HDAC8 is helpful to restrain the proliferation of
human cervical, colon and lung cancer cell lines while the upre-
gulation encourages cell proliferation and also prevents apoptosis
in hepatocellular cancer [14,45]. It has also been reported that
transcription factor SRY-box 4 (SOX 4/sex determining region Y)
activates HDAC8 promoter which is responsible for the expression
of HDAC8 in cancer cell lines [46e49]. PCI-34051 (9) [Fig. 8] was
found to be effective for the treatment of T-cell lymphoma and
leukemia. It was also found as specific cytotoxic agent for Jurkat,
HuT78 and Molt-4 cell lines. PCI-34051 (9) induces calcium-
mediated caspase-dependant apoptosis [50]. In case of solid state
cancer cell lines like A549 (lung), Rko (colon), U87 (glioma) and
MCF-7 (breast), the same treatment cannot be used to induce
apoptosis [50].
Upregulation of HDAC8 results in an overexpression of HDAC1
and HDAC6 in invasive breast tumor cells to promote invasion. It
also causes the overexpression of matrix metalloproteinase-9
(MMP-9) as evidenced in MCF-7 breast cancer cells [51]. The role
of HDAC8 in the formation of the crenial neural crest cell of mice
skull has also been observed [4]. Deletion of HDAC8 in mice causes
perinatal lethality due to instability of the skull [4]. In case of neural
crest-derived neuroblastoma, the expression of HDAC8 can be
correlated with tumor stage [52]. Specific inhibition of HDAC8 over
non-selective pan-HDAC inhibition executed promising results in
Fig. 4. Implications of HDAC8 in different Diseases.
219
neuroblastoma models as far as toxicity and efficacy in pre-clinical
trial was concerned [53e55] but inhibition of the other HDAC iso-
forms in neuroblastoma causes apoptosis of cells [56e58]. By
mediating the ubiquintin mediated-degeneration of telomerase 1B
(hEST1B) protein, HDAC8 also affects the human telomerase ac-
tivity basically through a phosphorylation function-dependant
process [4]. Moreover, along with inv(16) protein and other co-
repressors, HDAC8 activates acute myeloid leukemia-I (AML-I) by
regulating the genes responsible for the formation of abnormal
haematopoetic cell proliferation, similar to leukemia [59,60].
HDAC8 also reduces the tumor suppressor expression by upregu-
lating the Tap73 expression [61]. HDAC8-mediated downregulation
of suppressor of Cytokine Signaling 1/3 (SOSC1/3) expression cau-
ses the alteration of Janus kinase 2/signal transduction and acti-
vation of transcription (JAK2/STAT) while inhibition of HDAC8
provides hindrance in SOS1/3 mediated cell proliferation along
with the suppression of haematopoetic cell activity in myelopro-
liferative neoplasms [62,63]. Bcl-2 Modifying Factor (BMF) has a
significant role as it executes the methyl selenopyruvate-mediated
apoptosis of cells where methyl selenopyruvate works as HDAC8
antagonist. The HDAC8-STAT3 mediated regulations of BMF have a
crucial role in cellular apoptosis and cell proliferation [5,6]. A drop
in HDAC8 concentration or inhibition of HDAC8 enzymatic activity
reveals its effect on the proliferation of cells having p53 mutation in
them. This phenomenon clearly pointed out the influence of HDAC8
inhibitors for p53 mutation-carrying tumor adjuvants [4]. HDAC8
also helps to mould platform, carries the cytokines to the nucleus,
to act on a specific locus of DNA and affecting the cancer sensitive
220 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
genes expression [4].
The vital role of HDAC8 enzyme is also found in parasitic dis-
eases like schistosomasis (by Schistosoma sp. or Flatworm) [4].
Therefore, HDAC8 can be targeted to combat schistosomasis. The
significance of HDACs was elucidated while testing the Trichostatin
(TSA), a pan-HDAC inhibitor, into the schistosome larvae and adult
parasites. Application of TSA led to the death of larvae and adult
worms [4]. Nevertheless, effects of the deacetylation activity by
HDAC8 were also found in other viral infections like influenza A and
Uukuniemi virus [64]. The in vitro studies revealed the HDAC8
dependant increased endocytosis, acidification and penetration of
influenza A and Uukuniemi virus into the host cells but the regu-
lation of HDAC1 provides the opposite results [64]. The down-
regulation of HDAC8 and/or HDAC3 using silencing RNA (siRNA)
affects the pathway involving conversion of early endosomes to
lysosomes causing in profitless endocytosis and inadequate acid
transformation for viruses resulting into reduction of viral infection
[64].
Lower concentration of HDAC8 induces remodelling/refashion-
ing of microtubular network leading to the centripetal movements.
Hence, this phenomenon reveals the essential role of HDAC8 in
centrosomal designing and endosomal mobility mediated by
cohesion. The influence of the centrosomal self-deacetylation of the
microtubules and/or of regulators to the centrosomal cohesion for
viral entry into the host body is still a cloudy concept [4]. HDAC8, in
congenital malformation, has been spotted as a crucial enzyme for
deacetylation of SMC3. This is a cohesin subunit which helps in
binding two sister chromatids [4,16]. In the early mitotic phase of
cell division, HDAC8-mediated deacetylation of chromatin releases
acetylated SMC3 that induces the recycling of cohesin into the
succeeding cell cycles. However, the absence of HDAC8 activity
enhances the amusement of acetylated cohesin leading to the
diminished chromatid affinity. This produces defective
transcription-mediated symptoms like CdLS [16]. The relation be-
tween the proximal presence of mutated residues of the enzyme to
the active site and the reduction of HDAC8 activity has also been
proposed. The N-(phenyl carbamothioyl), an activator of HDAC8
specifically, restores the activity of mutants apart from those mu-
tants present near the active site. For the substrate binding, the
required stabilization of enzyme conformation is done by the
activator which is prevented due to the proximity of the mutant
and the active site [65].
The expression of HDAC8 has been specifically noticed in several
cancers like colon, lung and breast cancers, hepatocellular carci-
noma, pancreatic and gastric cancers, acute lymphocytic leukemia
(ALL) and acute myeloid leukemia (AML) along with childhood
neuroblastoma [5,15,62,63,66]. It is observed that RNAi-mediated
HDAC8 knockdown inhibits the cellular proliferation in several
cancers (such as human colon and lung cancer, gastric adenocar-
cinoma, leukemia and cervical cancer) [66e68]. Upregulation of
HDAC8 is found to inhibit the apoptosis and therefore, induces cell
proliferation in hepatocellular and castric carcinoma cell line [15].
The inv(16) fusion protein in association with HDAC8 represses
AML-I regulated gene transcription [69]. Moreover, the knockdown
of HDAC8 tends to the repression of HoxA5 that decreases the
HoxA5 dependant wild type mutant p53 expression [70]. The
ectopic expression of HDAC8 enhances the p53 transcription
whereas the HDAC8 inactivation may be effective for p53 mutation
containing tumor cells [7].
5. Structure of HDAC8
In 2004, the first crystal structure of HDAC8 enzyme was
explored [18]. It was observed that the carbonyl group of the sub-
strate acetyl-L-lysine coordinates to the Zn2þ ion and subsequently
forms hydrogen bond with the catalytic Y306 of the human HDAC8
[71e74]. The tandem histidine pair namely H142 and H143 amino
acid residues of HDAC8 is crucial for the stabilization of the
transition-state [75]. H142 serves as the general base catalyst
whereas H143 serves as both the general acid and the general base
catalysts [73] (Fig. 5).
The metal-bound water molecule is deprotonated by the histi-
dine to interact carbonyl function of acetyl-L-lysine. A tetrahedral
intermediate is therefore formed (Fig. 5). To collapse the tetrahe-
dral intermediate, another histidine residue is found to protonate
the amino-leaving group of the substrate acetyl-L-lysine. Finally,
products of lysine and acetate are formed (Fig. 5) [75]. Recently, the
structural and functional importance of the conserved glycine-rich
loop G302GGGY in the active site of HDAC8 has been explored [73].
This catalytic loop is crucial since missense and nonsense muta-
tions in this HDAC8 loop may lead to Cornelia de Lange Syndrome
(CdLS). The CdLS, a multiple congenital disease [76], results from
gene mutations regulated by HDAC8 [16] and other proteins [65]. A
child diagnosed with CdLS where different missense mutations in
HDAC8 such as G304R has been identified [65,73]. Porter et al. [73]
suggested that the glycine residues in the G302GGGY segment are
very crucial for the maintenance of the Y306 residue. Also, all
glycine residues especially G304 and G305 provide flexibility on the
G302GGGY loop as suggested by the molecular dynamics (MD)
simulation study [73]. This results in a transition of Y306 between
‘in’ and ‘out’ conformations. This transition of the catalytic Y306
residue might be modulated by the HDAC8 inhibitors. Residues like
G151, F152, H180, F208, M274 and Y306 of HDAC8 construct the
active site tunnel walls [77]. These mentioned amino acid residues
are generally hydrophobic and conserved in nature for the HDAC
class I isoforms. These help during the binding of an inhibitor
containing bulky hydrophobic linker to the HDAC8 enzyme. The
manifestation of the movement of F152, away from M274, occurs
which might open a distinctive HDAC8 specific sub pocket [77].
Although belonging to the class I HDAC family, there are a
number of differences present between other HDACs and HDAC8.
Those are following:
 Human HDAC8 is an X-linked protein which does not depend on
any co-complexes for the activity [78,79].
 The C-terminal protein binding domain of the other HDACs of
the class is absent for HDAC8 whereas the L1 loop of the
enzyme, closest to the active site is eminently flexible in nature
and can goes under conformational changes specific to the
substrate [18].
 The L1 and the L6 loops of HDAC8 along with its catalytic
tyrosine forms a pocket specific to HDAC8 isoform which re-
quires a “L” shaped structure of inhibitors for selective binding
with HDAC8. But for the other HDAC isoforms the presence of
the L1 and L6 loops hinders the binding of inhibitors with “L”
shaped structure [80].
 HDAC8 can also be differentiated from the other class I HDACs in
the size and composition of its N-terminal L1 loop which shapes
a large portion in one side of the active site and extended to the
protein surface [4,81].
 The non-histone proteins like cohesin, ERR-a or cortacin are
associated with the HDAC8 enzyme. This provides HDAC8 the
ability to control processes like microtubular integrity, chro-
matid separation, muscle contraction and energy homeostasis
[11,21].
 The amino acid forming the HDAC8 pocket is also similar with
other HDACs of class I exept that HDAC8 contains a methionine
whereas the other isoforms contains a leucin in place of meth-
eonine [18].
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Fig. 5. Schematic representation of the histone deacetylase 8 mechanisms.
 From the structural aspects, HDAC8 consists of a nuclear local-
ization sequence present between the catalytic domain of the
enzyme and serine binding motif in an end of the catalytic
domain. HDAC8 is the smallest isoform among the HDACs pre-
sent into the class I of the HDAC family. The negative regulation
of the HDAC8 catalytic function through the cAMP dependent
PKA phosphorylation of S39 proximal to the catalytic domain
[11].
Inside the catalytic domain, seven loops are present. The Zn2þ
ion is present between the Loop7 and Loop4 of the domain. The
Zn2þ ion is conserved with D(A,V,L,F)Hx~100D sequence where
D178, H180 and D267 (D,H and D of the sequence) ligate with the
catalytic Zn2þ ion. It has also been reported that the substitution of
HDAC8 Zn2þ ion with Fe2þ ion resulted enhanced HDAC8 activity.
This indicated to possibility of HDAC8 activities as a ferrous enzyme
for in vivo activity (Fig. 6) [81].
According to Somoza et al. [18], HDAC8 active site consists of a
long and narrow tunnel where the walls are comprised of F152,
F208, H180, G151, M274 and Y306 basically hydrophobic in nature.
In the end of the hydrophobic tunnel, the Zn2þ ion was bound to the
carboxylate oxygen atoms of D178 and D267 and H180 heterocyclic
nitrogen atom. The Y306, D183 and D176 have also been seen
important in the active site. From SAHA bound human HDAC8
crystal structure (PDB ID: 1T69) of the active site (Fig. 6), it has been
seen that the hydroxamate group of the compound forms cheletion
with the HDAC8 catalytic Zn2þ ion whereas the phenyl cap moiety
has been fit into the HDAC8 pocket. H142 and H143 as well as
phenylalanine are forming the wall of the lysine binding channel
while the Y306 and D178 interact with the ZBG of SAHA [81]. A list
of reported crystal structures of histone deacetylase 8 as per Protein
Data Bank (PDB) [82] record is depicted in Table 3.
221
6. An insight into the HDAC8 inhibitors
Recently, HDAC8 is emerged as an important druggable target
and HDAC8 inhibitors are useful to treat various diseases [1e3].
However, no isoform-specific HDAC8 inhibitor is available in
dosage form. Therefore, designing and discovery of potent HDAC8
inhibitors is a challenging task in the field of anticancer
therapeutics.
The chemical structures of reported HDAC8 inhibitors generally
possess three pharmacophoric features. These contain a surface
recognition function or a cap group, a hydrophobic cavity-binding
linker motif and a zinc-binding group (ZBG). This hydrophobic
cap group may be able to confer HDAC isoform-specific surface
recognition at the binding site rim. Hydroxamates are generally
utilized to synthesize HDAC8 inhibitors as this functional group
acts as a strong ZBG [1]. Hydroxamic acids as ZBG express high
affinity toward the catalytic Zn2þ and therefore, coordinate strongly
to the Zn2þ ion at the enzyme active site. Mostly, compounds
bearing hydroxamate moiety exhibit HDAC8 inhibiton in lower
nanomolar concentration. Nevertheless, the strong zinc chelating
ability of hydroxamic acid offers nonselective HDAC inhibition or
interacts with other zinc-dependent metalloenzymes such as
aminopeptidase N (APN) and matrix metalloproteinases (MMPs).
Moreover, these hydroxamate compounds display poor absorbtion
property in vivo. In these circumstances, researchers have paid their
attention to design non-hydroxamate (weak Zn2þ chelator in
comparison to hydroxamate) HDAC inhibitors. These non-
hydroxamate ZBGs contain different structural motifs such as car-
boxylic acids, boronic acids, thiols, oximes, trifluoromethyl ketones,
hydroxy-pyridin-2-thiones and b-lactams (Fig. 7). Compounds
possessing these non-hydroxamate ZBGs also yield effective HDAC8
inhibition.
222 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240

Fig. 6. Contours of different the ligand binding site of HDAC (HDAC8, HDAC6 and HDAC4) isoforms along with their catalytic Zn2þ and important amino acid residues for ligand
binding. (A) and (B) Ligand (SAHA) bound crystal structure of HDAC8 (PDB: 1T69), (C) Ligand binding site of HDAC4 (PDB: 2VQJ) and (D) Ligand binding site of HDAC6 (PDB: 5W5K).

In this section, hydroxamate and non-hydroxamate ZBGs con-
taining potential HDAC8 inhibitors are discussed and their selec-
tivity and nonselectivity have also been highlighted in details
(Table 4).
A series of cyclic hydroxamic acid containing peptides (CHAPs)
was reported by Furumai and co-workers [83]. These synthesized
CHAP derivatives enhanced the G1 cell population and decreased
the growth of HeLa cell at S phase. Importantly, the CHAP31 (1)
[Fig. 8] displayed good HDAC inhibition (IC50 ¼ 3.32 nM) obtained
from B16/BL6 melanoma.
Some cyclic tetrapeptide compounds having pentafluoroethyl
and trifluoromethyl ketone ZBGs were synthesized by Jose and co-
workers [84]. These compounds were tested against different
HDACs along with p21 promoter assay. Compound containing the
pentafluoroethyl ketone moiety (HDAC8 IC50 ¼ 780 nM) exhibited
lower HDAC8 inhibitory activity compared to the corresponding
trifluoromethyl ketone derivative (HDAC8 IC50 ¼ 370 nM). More-
over, compound possessing the trifluoromethyl ketone function
with a thioether linker was found to be the most effective com-
pound (2) (HDAC8 IC50 ¼ 230 nM). It may be probably due to the
proper coordination with the catalytic Zn2þ ion (Fig. 8). Compounds
containing b-lactam function was reported to display better HDAC
inhibition than sodium butyrate [85]. Such type of compounds also
triggered NF-kB mediated cytotoxicity during modulation of
HDAC8 inhibitory activity. A number of hydroxamate and mer-
captoacetamide small molecule HDAC inhibitors were synthesized
by Kozikowski et al. [86]. The thiol and carbonyl groups of these
compounds were found to contribute properly during Zn2þ chela-
tion. Compared to thiol, the hydroxamate group was proven to be
better ZBG (3, IC50 ¼ 1,050 nM) (Fig. 8).
Several active bis-(aryl)-type HDAC inhibitors were designed
and synthesized by Moradei et al. [87]. The 2-amino-5-aryl anilide-
based benzamide derivatives exhibited good HDAC1 and HDAC2
inhibition. Among these compounds, LAQ-824 (4) showed HDAC8
inhibitory potency with an IC50 value of 400 nM (Fig. 8). Arts et al.
[88] developed some 5-pyrimidinyl hydroxamic acid derivatives.
Among these compounds, R306465 (5) exhibited remarkable
class I HDAC inhibition. R306465 (5) [Fig. 8] showed 16-fold better
HDAC8 inhibition (IC50 ¼ 23 nM) in vitro than SAHA (FDA-01,
IC50 ¼ 370 nM) [Fig. 3]. By inspecting the ligand-bound HDAC8 X-
ray crystal structures, KrennHrubec et al. [89] designed some new
hydroxamates different from SAHA (1). These compounds, lacking
the linker function, were a few more folds selective toward HDAC8
over HDAC1 and HDAC6. The right angle structural conformation of
the best active compound in series (6, HDAC8 IC50 ¼ 300 nM) may
properly fit into the HDAC8 subpocket resulting in stronger HDAC8
binding (Fig. 8).
The triazolylphenyl-containing HDAC inhibitors, synthesized by
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240 223

Table 3
List of reported crystal structures of histone deacetylase 8 as per Protein Data Bank (PDB) record.

PDB Organism Inhibitor Substrate Form Residue Res. (Å) Year

1T64 H. sapiens TSA – WT 754 1.90 2004

1T67 H. sapiens M344 – WT 377 2.31 2004
1T69 H. sapiens SAHA – WT 377 2.91 2004
1VKG H. sapiens CRA 19156 – WT 754 2.20 2004
1W22 H. sapiens PSTB-Hydroxamate – WT 754 2.50 2004
2V5W H. sapiens e Acetylpeptide Y306F 791 2.00 2007
2V5X H. sapiens Hydroxamate – S39D 776 2.25 2007
3EW8 H. sapiens M344 – D101L 388 1.80 2008
3EWF H. sapiens e Acetylpeptide H143A 1572 2.50 2008
3EZP H. sapiens M344 – D101 N 776 2.65 2008
3EZT H. sapiens M344 – D101E 776 2.85 2008
3FO6 H. sapiens M344 – D101A 776 2.55 2008
3F07 H. sapiens APHA – WT 1164 3.30 2008
3F0R H. sapiens TSA – WT 1164 2.54 2008
3MZ3 H. sapiens M344 – WT/Co2þ 778 3.20 2010
3MZ4 H. sapiens M344 – D101/Mn2þ 778 1.85 2010
3MZ6 H. sapiens M344 – D101/Fe2þ 389 2.00 2010
3MZ7 H. sapiens M344 – D101/Co2þ 389 1.90 2010
3SFF H. sapiens Amino acid derivative – WT 378 2.00 2011
3SFH H. sapiens Amino acid derivative – WT 378 2.70 2011
3RQD H. sapiens Largazole thiol – WT 788 2.14 2011
4BZ5 S. mansoni e Acetylpeptide WT apo 1784 1.78 2013
4BZ6 S. mansoni SAHA – WT 1784 2.00 2013
4BZ7 S. mansoni M344 – WT 1784 1.65 2013
4BZ8 S. mansoni J1038 – WT 1784 2.21 2013
4BZ9 S. mansoni J1075 – WT 1784 2.00 2013
4CQF S. mansoni Marcapto acetamide – WT 1784 2.30 2014
4QA0 H. sapiens SAHA – C153F 778 2.24 2014
4QA1 H. sapiens M344 – A188T 1156 1.92 2014
4QA2 H. sapiens SAHA – I243 N 778 2.38 2014
4QA3 H. sapiens TSA – T311 M 778 2.88 2014
4QA4 H. sapiens M344 – H344R 389 1.98 2014
4QA5 H. sapiens e Acetylpeptide A188T/Y306F 788 1.76 2014
4QA6 H. sapiens e Acetylpeptide I243 N/Y306F 788 2.05 2014
4QA7 H. sapiens e Acetylpeptide H334R/Y306F 394 2.31 2014
4RN0 H. sapiens Largazole analog – S39D 778 1.76 2015
4RN1 H. sapiens Largazole analog – S39D 778 2.18 2015
4RN2 H. sapiens Largazole analog – S39D 778 2.39 2015
5D1B H. sapiens TSA – G117E 778 2.90 2015
5D1C H. sapiens e Tetrapeptide D233G/Y306F 790 1.42 2015
5D1D H. sapiens e Tetrapeptide P91L/Y306F 790 2.01 2015
5DC5 H. sapiens M344 – D176 N 778 1.94 2016
5DC6 H. sapiens e Tetrapeptide D176 N/Y306F 790 1.55 2016
5DC7 H. sapiens e Tetrapeptide D176/Y306F 790 2.30 2016
5DC8 H. sapiens e Tetrapeptide H142a/Y306F 790 1.30 2016
5FUE S. mansoni 3- benzamidobenzo hydroxamate – WT 1784 2.19 2016
5BWZ H. sapiens Droxinostat – S39E 778 1.59 2016
5FCW H. sapiens Hydroxamic Acid – WT 766 1.97 2016
5THS H. sapiens M344 – G302A 778 1.90 2016
5THT H. sapiens M344 – G303A 1556 2.40 2016
5THU H. sapiens M344 – G304A 778 1.95 2016
5THV H. sapiens M344 – G304A 778 1.86 2016
6HQY S. mansoni PCI-34051 – WT 1788 2.50 2018
6HRQ S. mansoni NCC-149 – WT 1788 1.85 2018
6HSF S. mansoni PCI-34051 – H292 M 1788 1.90 2018
6HSG S. mansoni NCC-149 – H292 M 1788 1.85 2018
6HSH S. mansoni Quisinostat – WT 1788 1.54 2018
6HSK H. sapiens Quisinostat – Mutant 160 2.10 2018
6HSZ S. mansoni Benzohydroxamate inhibitor 2 – WT 1788 2.37 2018
6HT8 S. mansoni Benzohydroxamate inhibitor 3 – WT 1788 2.50 2018
6HTG S. mansoni Benzohydroxamate inhibitor 4 – WT 1788 1.94 2018
6HTH S. mansoni Benzohydroxamate inhibitor 5 – WT 1788 1.95 2018
6HTI S. mansoni Benzohydroxamate inhibitor 6 – WT 1788 1.69 2018
6HTT S. mansoni Benzohydroxamate inhibitor 7 – WT 1788 1.75 2018
6HTZ S. mansoni Benzohydroxamate inhibitor 8 – WT 1788 1.84 2018
6HU0 S. mansoni Benzohydroxamate inhibitor 9 – WT 1788 1.75 2018
6HU1 S. mansoni Benzohydroxamate inhibitor 10 – WT 1788 2.00 2018
6HU2 S. mansoni Benzohydroxamate inhibitor 11 – WT 1788 1.99 2018
6HU3 S. mansoni Triazole hydroxamate inhibitor – WT 1788 1.65 2018

This table is based on the table reported by Amin et al. [1] and Chakrabarti et al. [4].
Data taken from Ref. [82].
224 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Fig. 7. Different reported zinc binder groups namely hydroxamates, trifluoromethyl ketones, thiols, boronic acids, carboxylic acids, oximes, hydroxy-pyridin-2-thiones and b-
lactams for HDAC8 inhibition.
Chen et al. [90] consisted of an interesting modification in their
cap region. Most of these compounds of this series were weaker
HDAC8 inhibitors among which compound 7 showed an IC50 of
406 nM. Though the selectivity profile was not much interesting,
these compounds exhibited good selectivity towards HDAC6
(Fig. 8). Kozikowski et al. [91] synthesized another series of
phenylisoxazole-containing hydroxamates as HDAC inhibitors with
greater selectivity towards HDAC6. These compounds also dis-
played some class I and class IIb HDAC inhibitory activity. Experi-
mental evidences suggested that these phenylisoxazole-based
compounds were potential HDAC8 inhibitors. Among these com-
pounds of the series, compound 8 (Fig. 8) yields the highest HDAC8
inhibition (IC50 ¼ 938 nM). Balasubramanian et al. [50] reported a
compound named PCI-34051 (9, HDAC8 IC50 ¼ 10 nM) which
exhibited highly potent HDAC8 inhibitory activity (Fig. 8).
Andrianov et al. [92] synthesized some hydroxamate-based
derivatives those had more potency against HDAC1 and HDAC6
compared to HDAC8 (10, IC50 ¼ 779 nM) [Fig. 9].
During in vivo pharmacodynamic analysis conducted on more
than 100 pyrimidyl hydroxamates, a molecule (JNJ-26481585, 11)
was recognized by Arts et al. [93]. This molecule showed good
HDAC1 (IC50 ¼ 110 mM) and HDAC2 (IC50 ¼ 330 mM) inhibitions but
highly potent and selective HDAC8 inhibition (11, IC50 ¼ 4.26 nM)
[Fig. 9]. Smil et al. [94] reported some HDAC6 selective chiral
HDAC8 inhibitors containing the 3, 4-dihydroquinoxaline-2-(1H)-
one and the piperazine-2,5-dione aryl hydroxamate (12,
IC50 ¼ 210 nM) scaffolds. Though these compounds dedicated their
activity against HDAC6, the structural information obtained from
these chiral inhibitors can be useful to design effective HDAC8 in-
hibitors with higher potency (Fig. 9).
Giannini et al. [95] synthesized a number of N-hydroxy-(4-
oxime)-cinnamate-derived cytotoxic HDAC8 inhibitors. Com-
pounds having bulky heteroaryl- or aryl-substituted oxime group
at the para position of the cinnamic acid moiety provided better
activity towards HDAC8 over other isoforms. The 4-nitrobenzyl
group containing compound (13, IC50 ¼ 70 nM) [Fig. 9] showed a
minimum of 2-fold HDAC8 selectivity over other HDAC isoforms.
Moreover, the 2-morpholinylmethyl analog (14) was also providing
a good HDAC8 activity (IC50 ¼ 235 nM) [Fig. 9]. Canzoneri et al. [96]
discovered some nuclear localization signal peptide (NLS)-derived
HDAC inhibitors. The lysine-enriched sequence of the NLS might
copy the histones core N-terminal Lys-tail. These NLS-derived
HDAC inhibitors helped in nuclear delivery and localization. They
synthesized NLS-derived peptide and 1, 2, 3-triazole moiety con-
taining hydroxamates. These experiments showed that the length
of the linker was an important component for inhibition of HDAC8
enzymatic activity (15, IC50 ¼ 1,243 nM) [Fig. 9].
Oyelere et al. [97] found out a new class of nonpeptide HDAC
inhibitors. These compounds were derived from the macrocyclic
backbone of macrolide antibiotics. Compounds containing these
scaffolds are not much active against HDAC8 (16, IC50 ¼ 994 nM)
but effective against HDAC1 and HDAC2 (Fig. 9). Montero et al. [98]
reported a pool of b-amino acid-containing compounds having
structural similarity with the cyclic tetrapeptide. Changes in the
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240 225

Table 4
List of hydroxamate and non-hydroxamate ZBGs containing potential HDAC8 inhibitors.

Sl No. Scaffold Most active isoform Best HDAC8 inhibitory activity References

Cpd No. IC50 (nM)

1 Peptide containing cyclic hydroxamic acid derivative e 1 3.32 [83]

2 Trifluoro methyl and tetrafluoro ethyl ketone based cyclic HDAC1, HDAC8 2 230 [84]
tetrapeptide derivative
3 Mercapto acetamide based hydroxamate HDAC6 3 1050 [86]
4 Amino phenyl benzamide based hydroxamate HDAC1, HDAC2 4 400 [87]
5 5-pyrimidinyl based hydroxamate HDAC1 5 23 [88]
6 4-napthyl-phenyl based linkerless hydroxamate HDAC8 6 300 [89]
7 Triazolyl based hydroxamate HDAC6 7 406 [90]
8 Phenyl iso-oxazole based hydroxamate HDAC6 8 938 [91]
9 Aryl hydroxamate derivative HDAC8 9 10 [50]
10 Amide derivative Pan HDAC 10 779 [92]
11 Pyrimidyl hydroxamate HDAC1, HDAC2 11 4.26 [93]
12 3,4-dihydroquinoxaline-2-(1H) one derivative HDAC6 12 210 [94]
13 Piperazine-2,5-dione aryl hydroxamate HDAC6 12 210 [94]
14 N-hydroxy-(4-oxime)-cinnamate based hydroxamate HDAC8 13 70 [95]
15 2-morpholinyl ethyl hydroxamate HDAC8 14 235 [95]
16 1,2,3-triazole based NLSP hydroxamate HDAC1, HDAC2 15 1243 [96]
17 Non peptide macrocyclic derivative HDAC1, HDAC6 16 994 [97]
18 Cyclic a/b tetra peptide derivative HDAC8 17 120 [98]
19 Benzyloxy phenyl carbamoyl hydroxamate HDAC-8 18 2710 [99]
20 a/b Cyclic tetra peptide HDAC6 17 133 [100]
21 Boronic acid-based derivative HDAC6 19 6600 [101]
22 2-piperazinyl-5- pyrimidyl hydroxamate Pan HDAC 20 e [102]
23 Acetyl urea based hydroxamate HDAC1 21 270 [103]
24 Triazole-4-yl phenyl based hydroxamate Pan HDAC 22 1190 [104]
25 Tricyclic ketolide based hydroxamate HDAC8 23 544.6 [105]
26 Cyclo peptide based hydroxamate HDAC1, HDAC2, HDAC8 24 23,000 [106]
27 Tetrahydro isoquinoline based hydroxamate HDAC8 25 580 [107]
28 Tetrahydro isoquinoline based hydroxamate HDAC6 26 47 [108]
29 Tetrahydro isoquinoline based hydroxamate HDAC6 27 146 [109]
30 Benzohydroxamate derivative HDAC8 28 23 [110]
31 Oxime amide derivative Pan HDAC 29 22,600 [111]
32 Gamma lactym derivative HDAC6 30 119.7 [112]
33 Gamma and del- lactum based hydroxamate HDAC3 31 17 [113]
34 1,4-dithia-7-aza spiro[4.4] nonane-8-carboxylate based derivatives HDAC8 32 21 [114]
35 Short chained(phenyl butyryl) based hydroxamate HDAC1 33 4000 [115]
36 SAHA derivative with osthole derived CAP region HDAC1 34 267.85 [116]
37 Ferrocinyl based JAHA derivative Pan HDAC 35 2 [117]
38 Amino acid derivative HDAC1, HDAC2 36 90 [70]
39 SAHA derivative HDAC6 37 220 [118]
40 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-N-hydroxy octane di-amide derivative HDAC1 38 1,400a [119]
41 Tetrapeptide derivatives without ZBG HDAC8 39 17 [120]
42 Cu(I) catalyzed azide alkyne cyclo addition library of HDAC8 inhibitors HDAC8 40 70 [121]
43 Alkoxamide linked hydroxamate HDAC4, HDAC5, HDAC6 41 893 [122]
44 Phenyl glycin based hydroxamate HDAC8 42 967 [123]
45 Quinazoline-4-one derivative HDAC6 43 420 [124]
46 3-Hydroxypyridin-2-thione derivative HDAC6 44 800 [125]
47 N-Methylpyrrole (Py)-N-methylimidazole (Im) polyamides HDAC1, HDAC2, HDAC8 45 130 [126]
(pips) derivative
48 Amide-linked p-substituted phenyl hydroxamate HDAC6 46 689 [127]
49 Carrbostyril derivative Pan HDAC 47 6 [128]
50 Triazole derivative HDAC8 48 53 [130]
51 Aminotetralin derivative HDAC6, HDAC8 49 30 [132]
52 1,2,4-oxadiazole containing 2-amino benzamide derivative HDAC1, HDAC2 50 200 [133]
53 Benzohydroxamate derivative HDAC6 51 3 [134]
54 Pteroate hydroxamide derivative HDAC6 52 581 [135]
55 Benzothiophene based hydroxamate derivative HDAC6 53 1400 [136]
56 Benzohydroxamate derivative HDAC6 54 376 [137]
57 Suberonyl hydroxamate derivative HDAC8 55 119 [139]
58 Glutamic acid derivative HDAC8, MMP-2 56 2890 [8]
59 Aminopyrrolidinone derivative HDAC6 57 80 [140]
60 1-hydroxypyridine-2-thione derivative HDAC8 58 980 [141]
61 2,5-Disubstituted-1,3,4-oxadiazole derivative HDAC8 59 98 [25]
62 Triazole analog HDAC8 60 0.8 [142]
63 Tetrahydro isoquinoline based hydroxamate HDAC1, HDAC3 61 44 [143]
64 N1-hydroxy tetrapthalamide based derivative HDAC8 62 5500 [26]
65 Propargylamine derivative HDAC6 63 417 [144]
66 Meta-sulfamoyl N-hydroxybenzamide derivative HDAC8 64 50 [145]
67 iso-Combretastatin based derivatives HDAC8 65 60 [146]
a
HDAC8 Kd value.
226 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240

Fig. 8. Structures of HDAC8 inhibitors (1-9).

Fig. 9. Structures of HDAC8 inhibitors (10-17).

 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
positions of b-3-amino acid, Zn2þ chelating amino acid group, the
amino acid chirality and the alkylation of backbone amide nitrogen
atom around the macrocyclic feature, were made to design selec-
tive HDAC inhibitors. Among these compounds, cpd 17 (Fig. 9)
resulted in potent HDAC8 inhibitory activity (IC50 ¼ 120 nM).
A series of triazole-4-yl substituted hydroxamate molecules
containing aryl cap group were synthesized and evaluated against
HDAC isoforms by He et al. [99]. Commonly, most of these com-
pounds were pan-HDAC inhibitors. However, some of them were
active in nanomolar concentration against HDAC isoforms like
HDAC1, HDAC3, HDAC6 and HDAC10. Cpd 18 provided poor HDAC8
inhibition (IC50 ¼ 2,710 nM) [Fig. 10].
Olsen and Ghadiri [100] developed some compounds bearing
cyclic tetrapeptide scaffold by keeping the same side chain motif
(17) [Fig. 9]. The hydroxamate group showed the most beneficial
effect while compared to other zinc binding groups. Compounds
containing boronic acid function also provided HDAC inhibition. As
far as the boronic acid derivatives were concerned, Suzuki et al.
[101] pointed out that the (S)-conformation of the compound had a
significant importance regarding HDAC inhibition. The derivative
though selective towards HDAC6 possessed very poor HDAC8 in-
hibition (19, HDAC8 IC50 ¼ 6,600 nM) [Fig. 10]. Angibaud et al. [102]
reported some substituted 2-piperazinyl-5-pyrimidylhydroxamic
acid derivatives as potent HDAC inhibitors. The biphenyl
substituted 2-piperazinyl-5-pyrimidylhydroxamate analog (20)
[Fig. 10] showed an excellent HDAC inhibition (IC50 ¼ 0.9 nM) with
a good antiproliferative property against human ovarian cancer
A2780 cell line (IC50 ¼ 29 nM). This compound (20) or the modifi-
cation of this compound can be effective against HDAC8.
Some acylurea-connected straight-chain hydroxamate de-
rivatives were reported as promising HDAC inhibitors by Wang
et al. [103]. Compound containing 5-carbon linker function
exhibited the best HDAC1 inhibition (IC50 ¼ 53 nM) but provided
poor HDAC8 inhibition (IC50 ¼ 608 nM). However, the compound
with 6-carbon linker function produced better HDAC8 inhibitory
Fig. 10. Structures of HDAC8 inhibitors (18-25).
227
potency (21, IC50 ¼ 270 nM) [Fig. 10]. In the series of the triazole-4-
yl phenyl based hydroxamate compounds synthesized by He et al.
[104], it was noticed that these compounds showed poor HDAC8
inhibition. Though these compounds were pan-HDAC inhibitors,
these were more selective towards HDAC3 and HDAC6. Among
these compounds, compound with cyclohexyl function (22)
showed a weak HDAC8 inhibition with an IC50 of 1190 nM (Fig. 10).
Mwakwari et al. [105] introduced tricyclic ketolide imitating the
macrocyclic peptide skeleton. These ketolide-based HDAC in-
hibitors showed HDAC1 and HDAC2 selectivity over other HDAC
isoforms. The best active compound was having a moderate HDAC8
inhibition (23, IC50 ¼ 544.6 nM) and might be targeted against the
tumor-associated macrophages (Fig. 10).
Terracciano and coworkers [106] isolated a compound named
FR235222 (24, IC50 ¼ 23,000 nM) from the fermented fungus broth
of Acremonium sp. This cyclopeptide molecule was synthesized by
the same group of workers showed potency against HDAC (Fig. 10).
In the development process of potent HDAC8 inhibitors, Zhang et al.
[106] synthesized and evaluated a pool of 1, 2, 3, 4-
tetrahydroisoquinoline-3-carboxylic acid compounds as potent
HDAC8 inhibitors. Among these compounds, 25 (Fig. 10) exhibited
good HDAC8 inhibition (IC50 ¼ 580 nM). Again, they developed a
new group of HDAC8 inhibitors having the tetrahydroisoquinoline
moiety as a linker [108]. Compound having the 4-methyloxyphenyl
group associated with the tetrahydroisoquinoline moiety and the t-
butoxycarbonyl (Boc) group showed higher contribution towards
HDAC8 inhibition (26, IC50 ¼ 47 nM) (Fig. 11).
Zhang et al. [109] further optimized the previously derived lead
compound to synthesize a compound ZYJ-34c (27) having tetra-
hydroisoquinoline scaffold (Fig. 11). Cpd 27 was orally active and
more potent HDAC8 inhibitor compared to the FDA-approved SAHA
(FDA-01) [Figure-3]. Cpd 27 (ZYJ-34c) also exhibited higher in vivo
antitumor potency against human breast cancer MDA-MB-231-
xenograft model [109]. It also showed efficacy against mouse
hepatoma-H22 pulmonary metastasis as well as human colon
228 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Fig. 11. Structures of HDAC8 inhibitors (26-37).
cancer HCT116 xenograft model [109]. Tang et al. [110] employed an
unique two step protocol to design selective HDAC8 inhibitors and
discovered a group of benzohydroxamic acid based compounds as
potent and selective HDAC8 inhibitors. In an in vitro study of these
compounds against HDAC2, HDAC3 and HDAC8 enzymatic activity
the compounds actually provided promising results. The com-
pounds were remarkably selective along with excellent sub nano-
molar potency toward HDAC8 enzymatic activity that HDAC2 and
HDAC3. The most active compound of series (28) [Fig. 11] was able
to exhibit a good activity (IC50 ¼ 23 nM) against HDA8 and was 15
fold and 65 fold selective toward HDAC8 than HDAC2 and HDAC3
respectively.
Botta et al. [111] reported effective HDAC inhibitors by modi-
fying the ZBG with oximes. As per their observations through
computational analysis, it was noticed that the a-oxime as a ZBG
perfectly adapted in the active site for coordinating to the Zn2þ ion.
Cpd 29 bearing the a-oxime function exhibited HDAC8 inhibition of
IC50 ¼ 22,600 nM (Fig. 11).
A number of g-lactum based compounds were derived and
evaluated by Choi and co-workers [112]. These compounds exerted
promising class I and class II HDAC inhibition but tended to be more
effective against HDAC6. Cpd 30 (Fig. 11) showed the best HDAC6
inhibition (IC50 ¼ 0.8 nM) with an acceptable HDAC8 inhibition
(IC50 ¼ 119.7 nM). Neelarapu et al. [113] synthesized a number of
diazide-containing isoxazole- and pyrazole-derived compounds as
HDAC inhibitors. Compounds bearing pyrazole scaffold showed
good HDAC3 and HDAC8 inhibition. Among these compounds, cpd
31 (Fig. 11) resulted in a good HDAC8 inhibition (IC50 ¼ 17 nM).
Zhang et al. [114] designed and synthesized a new class of tri-
peptidomimetics having good HDAC8 inhibitory profile. Compound
possessing the 1, 4-dithia-7-azaspiro- [4,4]-nonane-8-carboxylic
acid as the cap group and 6-aminohexanoic acid as the linker
function was the most potent HDAC8 inhibitor (32, IC50 ¼ 21 nM)
among these compounds [Fig. 11]. Fass et al. [115] attempted to
develop some short-chain hydroxamic acids with potential HDAC
inhibitory activity. Compound containing hydroxamate as the ZBG
having phenyl ring as the cap group showed the best HDAC8 in-
hibition (33, IC50 ¼ 4000 nM). However, it was more effective
against HeLa HDAC (IC50 ¼ 600 nM) [Fig. 11]. Compounds contain-
ing the aryl cap group was found to be preferable than compounds
with the linear alkyl chain as far as the HDAC8 inhibition was
concerned.
Huang et al. [116] reported some osthole-based SAHA-linked
hydroxamates as effective and selective HDAC8 inhibitors
compared to HeLa HDACs. Cpd 34 among these compounds exerted
the most potent HDAC8 inhibitory activity (IC50 ¼ 267.85 nM)
[Fig. 11]. It is better than SAHA (FDA-01) [Fig. 3]. Spencer et al. [117]
synthesized Jay Amin hydroxamic acid (JAHA, 35, HDAC8
IC50 ¼ 2 nM), an organometallic analog of SAHA with the ferrocenyl
group as the phenyl bioisostere. It had promising class I HDAC
inhibitory property (Fig. 11). A number of potential chiral a-amino-
ketone-based HDAC8 inhibitors were reported by Whitehead and
co-workers [70]. One of these compounds comprising dichlor-
ophenyl group showed potent HDAC8 inhibition (36, IC50 ¼ 90 nM)
with a minimum of 20-fold selectivity over HDAC1, HDAC2 and
HDAC6 (Fig. 11). Guerrant et al. [118] explored some dual inhibitors
of HDACs and topoisomerase-II by combining two prototype
chemotherapeutic agents (SAHA and anthracycline analogs). Few of
them showed medium to poor HDAC8 inhibition. Cpd 37 among
these bifunctional compounds was the most potent HDAC8 inhib-
itor (IC50 ¼ 220 nM) (Fig. 11). Henkes et al. [119] modified the linker
spacer of SAHA with the perfluorinated alkyl function. They ana-
lysed the effect of this spacer on different HDACs. Compound
bearing the anthracene ring (38, HDAC8 Kd value ¼ 1,400 nM) were
more active than SAHA (HDAC8 Kd value ¼ 2,900 nM) against
HDAC8 (Fig. 12) [119].
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Fig. 12. Structures of HDAC8 inhibitors (38-49).
Vaidya et al. [120] derived some tetrapeptide derivatives and
evaluated them against HDAC isoforms. This study revealed the
importance of hydroxamate ZBG group for imparting the HDAC
inhibitory activity. Cpd 39 showed potent in vitro HDAC8 inhibitory
activity (IC50 ¼ 17 nM) (Fig. 12). Using the click chemistry-based Cu
(I)-catalyzed-azide-alkyne cycloaddition (CuAAC), a library of
HDAC8 inhibitors was synthesized by Suzuki et al. [121]. This study
resulted in selective and potent HDAC8 inhibitor 40 (IC50 ¼ 70 nM)
[Fig. 12]. Marek et al. [122] reported synthesis and HDAC inhibitory
activity of some alkoxamide-linked hydroxamates. These com-
pounds possessed not much potency against HDAC8 but cpd 40
showed comparatively effective HDAC8 inhibition (41,
IC50 ¼ 893 nM) [Fig. 12].
Zhang et al. [123] synthesized some arylhydroxamic acids as
potential HDAC8 inhibitors. Compounds containing the ortho and
para-substituted phenyl rings were poor HDAC8 inhibitors. The 3-
trifluorophenyl analog showed the most potent HDAC8 inhibition
(42, IC50 ¼ 967 nM) [Fig. 12]. During an attempt to develop selective
HDAC inhibitors for the treatment of Alzheimer's disease Yu et al.
[124] synthesized some quinazoline-4-one derivated compounds
as HDAC inhibitors. The compounds were highly selective toward
HDAC6 but also appeared to possess promising HDAC8 inhibition.
The compound 43 delivered the highest in vitro HDAC8 inhibition
(HDAC8 IC50 ¼ 420 nM) and was almost equipotent to HDAC6
enzymatic activity [Fig. 12]. By means of Suzuki cross-coupling
reactions, Patil et al. [125] reported some new HDAC inhibitors
comprising aromatic and heteroaromatic moiety with 3-hydroxy-
pyridin-2-thione (3-HPT) group as effective ZBG. Among these
compounds, the p-methyl biphenyl derivative exhibited the most
potent HDAC8 inhibition (44, IC50 ¼ 800 nM) [Fig. 12].
Saha et al. [126] derived some new type of HDAC8 inhibitors
with pyrrole-imidazole polyamides (PIP) conjugates. The derivative
of JAHA complexed with PIP-d (JAHA-PIP-d, 45) showed excellent
HDAC8 inhibition (IC50 ¼ 130 nM) [Fig. 12]. Wagner et al. [127]
229
reported some compounds having the amide-linked p-substituted
phenyl hydroxamic acid and evaluated against HDAC2, HDAC4,
HDAC6 and HDAC8 enzymes. The ethylene-piperazine function as
the cap group (HDAC8 IC50 ¼ 21,000 nM) provided poor activity
against HDAC8. Further, activity of these compounds was increased
by reducing the chain length from the phenethyl group (HDAC8
IC50 ¼ 1,150 nM) to the benzyl function (HDAC8 IC50 ¼ 1,030 nM)
and also from the benzyl to the phenyl function (46, HDAC8
IC50 ¼ 689 nM) [Fig. 12]. The activity profile against HDAC8 was
decreased in case of the 4-methylamide analog (HDAC8
IC50 ¼ 1950 nM) compared to the 4-phenyl hydroxamic acid.
Tashima et al. [128] designed and synthesized 15 carbostyril de-
rivatives with promising HDAC inhibitory activity. The amide linker
(1-CONH) and the corresponding reverse amide (1-NHCO) between
the cap group and the ZBG displayed some important hydrogen-
bonding interactions with HDAC enzyme. The best HDAC8 inhibi-
tory potency was shown by cpd 47 (IC50 ¼ 6 nM) [Fig. 12]. Ononye
et al. [129] synthesized some a- and b-tropolones as highly effec-
tive and selective HDAC2 inhibitors over HDAC1, HDAC4-6 and
HDAC8. These compounds also showed good HDAC8 inhibition.
In an attempt to increase the efficacy of NCC-149 (40, HDAC8
IC50 ¼ 70 nM) [Fig. 12], Suzuki et al. [130] modified the aryl linker of
the scaffold with different heterocyclic aryl groups such as triazole,
thiophene, etc. They found a compound with the modified triazole
orientation showed slight increase in the HDAC8 inhibitory potency
(48, IC50 ¼ 53 nM) [Fig. 12]. A series of biphenylacrylohydroxamic
acids as HDAC inhibitors (particularly HDAC6) was synthesized by
Cincinelli et al. [131]. The influence on HDAC8 inhibition was
observed by studying these compounds with the adamantyl or
without the adamantyl moiety. Interestingly, incorporation of an
adamantyl moiety was not effective for HDAC8 inhibition. Though
the hydrophobic functionality was favourable in cap region, an
unexpected decrease in the HDAC8 and other HDAC isoforms was
observed for compounds containing adamantyl cap group.
230 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Tang et al. [132] brought a new class of aminotetralin-linked
dual inhibitors of HDAC6 and HDAC8. Among these compounds,
cpd 49 showed most potent HDAC inhibitory activity (HDAC8
IC50 ¼ 30 nM) (Fig. 12). Cai et al. [133] synthesized two series of 2-
aminobenzamides and hydroxamates which showed significant
in vitro antiproliferative activity against NCI-H661, U937, A549,
MDAMB-231 and HCT-116 cancer cell lines. The hydroxamate de-
rivatives showed an excellent HDAC8 inhibition and selectivity over
HDAC1 and HDAC2. These hydroxamates showed the importance of
the phenyl ring as the cap group for HDAC8 inhibition (50,
IC50 ¼ 200 nM) [Fig. 13]. In a successful effort to enhance the po-
tency of HDAC6 inhibitors, Shen and his co-workers [134] were able
to synthesize a series of bicyclic cap group containing benzohy-
droxamate derivatives with higher affinity toward HDAC6 inhibi-
tion. The most active compound (51) [Fig. 13] of this series was
exhibited an inhibitory activity of IC50 ¼ 3 nM against HDAC6 and
with a decent nanomolar activity (IC50 ¼ 176 nm) against HDAC8
enzymatic activity. Two folic acid and pteroic acid based hydrox-
amate derivatives were designed and synthesized by Sodji et al.
[135] and were analysed against in vitro HDAC1, HDAC6 and HDAC8
enzymatic activity. The observation of this experiment highlighted
the folic acid derivative as totally inactive against all three HDAC
isoforms whereas the pteroic hydroxamate derivative (52) [Fig. 13]
was excellently inhibited HDAC6 (IC50 ¼ 17.6 nM) along with
moderate activity against HDAC8 (IC50 ¼ 581 nM) and poorly
inhibited HDAC1 enzymatic activity (IC50 ¼ 2,390 nM). Further
modification of the linker motif of the compound was attempted
but was unable to provide promising activity against the selected
HDAC isoforms. De Vreese et al. [136] synthesized some benzo-
thiophene cap group containing hydroxamate derivatives as potent
HDAC inhibitors. The compounds clearly suggested that the 4-
bromo substitution in the fused benzothiophene phenyl ring was
unfavourable than its unsubstituted analog. The compound 53
(Fig. 13) was 1,400 nM active against HDAC8 enzymatic activity but
was more selective toward HDAC6 than HDAC8 isoform. In order to
Fig. 13. Structures of HDAC8 inhibitors (50-61).
design newer HDAC6 inhibitors Lee et al. [137] synthesized HPB
(54) [Fig. 13], a benzohydroxamate derivative for selective HDAC6
inhibition. The compound appeared to have higher HDAC6 inhibi-
tory activity and was also effectively inhibited cellular growth in
both tumor and normal cells without inducing apoptosis in normal
cells [137,138]. The compound was also provided a nanomolar ac-
tivity against HDAC8 (IC50 ¼ 376 nM). Further modification and
redesigning of newer molecules from this compound can help to
discover potent dual inhibitors of HDAC6 and HDAC8.
To design and synthesize some SAHA analogs, Zhang et al. [139]
reported some SAHA derivatives having comparatively better
HDAC8 binding affinity (PDB: 1T69) than SAHA (FDA-01, Fig. 3). Cpd
55 (Fig. 13) with the trifluoromethyl group at the third position and
the chlorine atom at the sixth position of the phenyl ring provided
the highest HDAC inhibitory potency among these molecules.
Halder et al. [8] reported some isoglutamine derivatives as dual
inhibitors of MMP-2 and HDAC8. Cpd 56 showed the most potent
HDAC8 inhibiton (IC50 ¼ 2,890 nM) and exhibited anti-migratory
and anti-invasive properties tested in human lung carcinoma
A549 cell line (Fig. 13). In an attempt to design orally bioavailable
HDAC6 inhibitors, Lin et al. [140] designed and synthesized some
aminopyrrolidinone derivatives as potent HDAC6 inhibitors. The
best active compounds provided an excellent HDAC6 inhibition
along with an excellent HDAC8 inhibition (57, IC50 ¼ 80 nM)
[Fig. 13]. It also strongly induced the acetylation of tubulin and
minimized the p21 levels. Some compounds containing 1-
hydroxypyridine-2-thione (1-HPT) group as ZBG was synthesized
and evaluated by Muthyala and co-workers [141]. Molecular
docking and molecular dynamic (MD) simulation study strongly
validated the binding pattern of these compounds with HDAC8.
These compounds were found to form an octahedral structure
while coordinating with the catalytic Zn2þ ion of HDAC8. Com-
pound 58 exhibited effective HDAC8 inhibitory activity
(IC50 ¼ 980 nM) [Fig. 13].
Pidugu et al. [25] synthesized some glycine or alanine linked
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240 231

oxadiazole derivatives having excellent class I HDAC inhibitory
activity. Cpd 59 (Fig. 13) showed the maximum in vitro HDAC8 in-
hibition (IC50 ¼ 98 nM) among these compounds. It also showed
effective in vitro antiproliferative activity against MDA-MB-231
breast cancer cell line (IC50 ¼ 230 nM) better than SAHA
(IC50 ¼ 6,000 nM). Ingham et al. [142] discovered selective HDAC8
inhibitors from a large set of small molecule library of Boston
University Centre for Molecular Discovery. Initially, they screened a
diverse set of 134 esters and subsequently converted these into a
total of 120 hydroxamic acids and methyl hydroxamates. This study
led to the development of a highly potent HDAC8 inhibitor namely
OJI-1 (60, HDAC8 IC50 ¼ 0.8 nM) [Fig. 13]. Cpd 60 was identified as
the most potent and selective HDAC8 inhibitor till now over all
other HDACs (HDAC1 to HDAC7 and HDAC9).
Taha et al. [143] reported some tetrahydroisoquinoline based
derivatives. These compounds showed the importance of the
number of carbon atoms in the alkyl chain contributing effectively
towards HDAC8 inhibition. Hydroxamate derivative containing 4
carbon atoms at the alkyl chain length showed the maximum
in vitro HDAC8 inhibitory potency (61, IC50 ¼ 44 nM). However,
most of these compounds were selective towards HDAC1 and
HDAC3 (Fig. 13). The N1-hydroxytetrephthalamide-based mole-
cules showed promising HDAC inhibition in which the indole cap
containing panobinostat (FDA-04, Fig. 3) and quisinostat (JNJ-
26481585, 11) (Fig. 9) are in clinical trials [1]. Wang et al. [26]
combined both scaffolds and reported the indole cap containing
N1-hydroxytetrephthalamide derivatives. Cpd 62 (Fig. 14) showed
promising HDAC inhibitory activity (IC50 ¼ 74 nM) though this
molecule was comparatively HDAC8 inhibitor (IC50 ¼ 5,500 nM). A
group of propargylanime derivatives were synthesized by Wünsch
et al. [144] to inhibit Zn2þ containing HDAC isoforms. The com-
pounds were seemed to provide a decent inhibitory activity against
HDAC8 though it was more selective toward HDAC6 and HDAC1
isoforms. The compound 63 (Fig. 14) was able to provide the highest
HDAC8 inhibition (IC50 ¼ 417 nM) among the compounds of this
series.
Zhao et al. [145] synthesized a group of potent HDAC8 selective
meta-sulfamoyl N-hydroxybenzamide derivatives among which
cpd 64 provided the best in vitro HDAC8 inhibition (IC50 ¼ 50 nM)
[Fig. 14]. In a recent study on HDAC inhibitors, Lamaa et al. [146]
designed and synthesized a number of iso-combretastatin based
compounds with inhibitory activity on different HDAC isoforms.
The in vitro test results of these compounds against HDAC6, HDAC8
and HDAC11 enzymatic activity displayed these compounds more
selective toward HDAC8 than HDAC6 and HDAC11 isoforms. Cpd 65
delivered the highest HDAC8 inhibitory activity (IC50 ¼ 60 nM) than
the other compounds of the series. Cpd 65 (Fig. 14) was also tested
on different tumor cell lines and was appeared to provide a
promising antiproliferative activity against HCT 116 (GI50 ¼ 8 nM),
A549 (GI50 ¼ 22 nM), K562 (GI50 ¼ 20 nM), PC3 (GI50 ¼ 28 nM), U87
(GI50 ¼ 8 nM), MCF-7 (GI50 ¼ 8 nM) and MiaPaca2 (GI50 ¼ 18 nM)
cell lines [146].
7. QSAR studies on HDAC8 inhibitors
Among the possible adaptable approaches for the identification
and discovery of molecules with optimistic biological potential,
quantitative structure activity relationship (QSAR) study is one of
the beneficial methods for identification and designing of potent
and selective inhibitors. For the past few years, different compu-
tational methodologies and statistically validated QSAR approaches
have been employed for screening and identification of molecules
with promising HDAC8 inhibitory activity and also for identification
of structural features beneficial for HDAC8 inhibition. A number of
QSAR studies have been conducted for the identification and
screening of potent HDAC8 inhibitors (Table 5).
In 2009, Ortore and co-workers [147] conducted a rational
docking-based 3D-QSAR study on a diverse set of 48 hydroxamate
derivatives to procure potent HDAC1 and HDAC8 selective in-
hibitors. This set of molecules also included ligands like TSA, vor-
inostat and MS-344. From the study, authors concluded that the
activity of these compounds may be dependable on a few things
such as the hydrogen bond formation between the compound and
the enzyme, polar interaction between the compound and D101
amino acid residue of HDAC8. The aromatic stack interaction
involving a phenylalanine residue of the enzyme might also cause

Fig. 14. Structures of HDAC8 inhibitors (62-65).

232 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240

Table 5
QSAR studies recently conducted on HDAC8 inhibitors.

Sl. No. Scaffold QSAR Technique Year Reference

01 Diverse Hyderoxamates Docking based 3D QSAR 2009 [147]

02 Diverse molecules Pharmacophore based 3D QSAR 2010 [148]
03 Diverse molecules 3D QSAR Pharmacophore mapping 2014 [149]
04 Diverse molecules Lazy learning-based classification QSAR 2015 [150]
05 Diverse compounds Pharmacophre-based 3D QSAR 2015 [8]
06 Diverse compounds Regression-based 2D QSAR, Pharmacophore-based 3D QSAR 2015 [151]
07 Diverse molecules SVC and SVM-based 2D QSAR 2016 [152]
08 SAHA derivative MLR based 2D-QSAR, Gaussian kernel based non-linear SVM 2D QSAR 2016 [153]
09 N-hydroxyfurylacrylamides DFT based MLR and ANN 2D QSAR 2016 [154]
10 Aryl valporic acids MLR 2D QSAR, Feed forward ANN 2D QSAR 2017 [155]
11 Diverse hydroxamates Pharmacophore based 3D QSAR 2017 [156]
12 Diverse molecules DFT based pharmacophore dependant 3D QSAR 2018 [157]
13 Diverse compounds Fragment based Bayesian classification QSAR 2018 [3]

HDAC1/HDAC8 selectivity [147]. The 3D-QSAR study also suggested

that these compounds with short indole linker and non-linker
molecules with more than one phenyl or aromatic ring might
provide HDAC8 selectivity.
Another study was conducted by Thangapandian et al. [148]
with the intention of designing novel HDAC8 inhibitors through a
pharmacophore-based 3D-QSAR analysis. They generated a couple
of pharmacophore hypothesis. These models were developed using
features like hydrogen bond acceptor (HBA), hydrogen bond donor
(HBD), metal binding group and hydrophobic features. The results
suggested six pharmacophore features as important components of
these compounds for better protein-ligand interaction between
HDAC8 enzyme and its inhibitors. The model suggested the HBA
and the HBD groups as the zinc binding features (ZBG) of these
compounds whereas the HY (hydrophobic) feature was suggested
to be a better fit as cap group for interaction with the surface res-
idues of HDAC8 pocket. The second pharmacophore model found to
contain two hydrophobic features, one acting as the cap group and
the other one as the linker spacer between the cap and the ZBG
[148].
Debanath et al. [149] applied a pharmacophore-based 3D-QSAR
study on a diverse set of 20 molecules with HDAC8 inhibitory ac-
tivity. Authors reported that the best pharmacophore hypothesis
containing hydrogen bond acceptor (HBA), hydrogen bond donor
(HBD) and ring aromatic (RA) features provided the regression
coefficient (R2) of 0.982 and leave-one-out regression coefficient
(Q2LOO) of 73.14% with 15.34% standard deviation (SD) [149]. The
pharmacophoric features of the selected models signify the pres-
ence of such features in these compounds to provide a good
protein-ligand interaction for HDAC8. It might be possible that the
indolyl ethyl moiety acts as the cap group, the hydroxamate group
as ZBG along with the ring aromatic features of the cpd 66 (Fig. 15)
as the linker moiety of the molecule to deliver the HDAC8
inhibition.
The constructed 3D-QSAR model yielded a R2 of 0.969 and a
standard deviation of 0.144 along with a Q2 (R2CV) of 0.712. It also
identified the presence of HBD group near the indole nitrogen
atom. The hydroxamate group and the linker nitrogen atoms are
favourable for HDAC8 inhibition. The hydrophobic region predicted
as favourable near the indolylethyl and phenyl linker moiety. The
electron withdrawing groups were also suggested to be favourable
for the compounds near the nitrogen atoms and the ZBG group.
In order to screen potential molecules for HDAC8 inhibition, Cao
et al. [150] performed a lazy-learning based classification QSAR
study on a diverse set of 75 molecules including 38 inhibitors and
37 non-inhibitor compounds. These compounds were screened on
the basis of their inhibitory potency toward HDAC8. From this
study, five molecules such as AW00409 (67), HTS03338 (68),
Fig. 15. Schematic representation of the pharmacophoric features of compound 66.
JFD03558 (69), KM00731 (70) and KM02921 (71) have been
screened as the lead compounds for HDAC8 inhibition (Fig. 16)
[150].
Halder et al. [8] conducted some structure-based and ligand-
based 3D-QSAR pharmacophore mapping study on a diverse set
of molecules in order to design dual inhibitors of HDAC8 and
MMP2. Based on the best pharmacophore hypothesis constructed
with a hydrophobic, a HBA and two hydrogen bond acceptor lipid
(HBAL) features, they designed and synthesized some glutamate
derivatives possessed both HDAC8 and MMP-2 inhibitory potency.
A regression based 2D-QSAR and pharmacophore-based 3D-
QSAR studies using 16 inhibitors with class I HDAC inhibitory ac-
tivity including HDAC8 inhibitory potency was carried out by Noor
et al. [151]. They reported the best 2D regression based model for
HDAC8 inhibition using 5 different descriptors that provided the R2
of 0.98 with a standard error (SE) of 0.24. The 2D-QSAR model
suggested that higher molecular polarizibility of these molecules
can be detrimental toward their HDAC8 inhibitory activity. The
lipophilicity (logP) of these molecules seemed to be beneficial for
their activity. The polar surface area of the molecules (Topological
polar surface area/TPSA) was also positively correlated with their
HDAC8 inhibitory activity whereas the number of hydrogen bond
acceptor groups (HBA) was negatively correlated with the activity.
Moreover, through the screening process 10 molecules (72-81)
[Fig. 17] were identified as lead molecules which might possess
potent HDAC inhibitory activity [151].
Cao et al. [152] further implemented the QSAR technique in a
hybrid strategy for screening and identification of novel HDAC in-
hibitors along with the molecular dynamics (MD) simulation study.
In this study, they applied a support vector component (SVC) and
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240 233

Fig. 16. Structures of the compound 67-71 screened as lead compounds for HDAC8 inhibition.

Fig. 17. Structure of molecule 72-81 screened as lead compounds for HDAC8 inhibition.

support vector machine (SVM) based classification QSAR technique
on a diverse set of 80 HDAC8 inhibitors. The SVC model provided a
93.33% accuracy rate with a 100% true positive rate (TPR) and
13.33% of false positive rate (FPR) for the training set along with 84%
accuracy on test set. The SVM model provided 74% regression
coefficient with 76.67% accuracy and predicted 76% of the accuracy
for the test set. Through the SVM model, 8 different physico-
chemical parameters of these molecules were identified which
might have influence on the HDAC8 inhibitory activity of these
compounds such as XlogP, TPSA, Span, Inertia Y, H_Don, N_Atoms and
234 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Inertia Z [152]. Using the screening process out of 59,652 molecules
only two lead molecules were identified as promising hit com-
pounds for effective HDAC8 inhibition [152].
Praseetha et al. [153] performed a multiple linear regression
(MLR) based 2D QSAR and Gaussian karnel aided SVM based 2D
QSAR models on 1, 2, 4-oxadiazole containing SAHA derivatives.
The constructed MLR model with 5 descriptors resulted in an R2 of
0.945, cross validated R2 (R2CV) of 0.905 with a mean error of 0.067.
The SVM aided model yielded an R2 of 0.990, R2CV of 0.923 with
mean error of 0.017 containing 5 different descriptors. The MLR and
SVM model both suggested the importance of 3D-MoRSE de-
scriptors (Mor32e and Mor09u) for these compounds for their
HDAC8 inhibitory activity [153]. The linear model signified the
importance of Mor32e by suggesting the increase of atomic elec-
tronegativity may be beneficial for HDAC8 inhibition of these
compounds. Moreover, JGI7 which also indicating toward the
reduction of molecular topological charge (lower values of JGI7)
may be possible to enhance HDAC8 inhibitory activity of the com-
pounds. The descriptor L3s and R5eþ also established negative
correlation with the HDAC8 inhibitory activity of the compounds
[153].
Tassine and Elhallaoui [154] applied the density function theory
(DFT)-based calculations on a dataset of 38 N-hydroxyfurylamide
HDAC8 inhibitors. The MLR model provided a correlation coeffi-
cient value of 0.800 with a standard deviation value of 0.288
whereas the artificial neural network-based 2D-QSAR model pro-
duced a correlation coefficient of 0.980. The MLR model was con-
structed using a total of five independent variables. The equation
indicated the negative correlation with the total energy of mole-
cules and positively correlated with the hardness. The melting
point of the dataset compounds were also contributed negatively
toward the HDAC8 inhibitory activity of these molecules. The
equation was also suggested that the lesser ionization potential and
higher electron affinity of these molecules were preferable for the
higher HDAC8 inhibition [154].
A molecular modelling study on aryl valporic acid HDAC8 in-
hibitors was conducted by Martinez-pacheco and co-workers [155].
They used the MLR 2D-QSAR analysis and feed forward artificial
neural network (ANN) technique to develop and optimize the 2D
Fig. 18. (A) Schematic representation of the 3D-QSAR study on the most active (83) and the least active compound (84) of the dataset. (B) Structure of two hit molecules (85-86)
screened in the study. (C) Structure of valporic acid derivative DAVP042 (82) identified as lead molecule for HDAC8 inhibition.
QSAR model. In this study, 40 hydroxamate derivatives were used
as the training set compounds to develop the 2D-QSAR models
whereas 500 aryl valporic acid derivatives, designed by the authors
were used as the test set compounds. These test set compounds
were designed with a ZBG, a spacer group along with a lipophilic
tail in their structure. The docking technique using Autodock 4.2
software was employed to perform docking of these molecules in
3D-structure of HDAC8 (PDB ID-3F07) in order to screen these
compounds [155]. A pool of 1194 descriptors including 1179 de-
scriptors calculated by Dragon software, 10 quantum descriptors
and 5 molecular descriptors procured from the blind docking was
used to carry out the QSAR study [155]. As a result of this study one
lead aryl valporic acid derivative DAVP042 (82) [Fig. 18(C)] was
identified as a hit molecule and tested on in vitro human cancer cell
lines such as A549, MCF-7, HCT-116 and U937. The compound
(DAVP042) exhibited highest potency against HCT-116 cell line and
was least potent in A549 cell line. Moreover, it provided moderate
anti proliferative activity in MCF-7 and U937 cell lines [155].
A pharmacophore based 3D-QSAR model was constructed by
Manal et al. [156] on a series of hydroxamic acid derivatives with
potent HDAC8 inhibitory activity. The best generated pharmaco-
phoric hypothesis resulted in the R2 of 0.850 with an external cross
validated R2 of 0.890. The model was consisted with five pharma-
cophoric features such as a hydrogen bond donor (HBD), a ring
aromatic (RA) and three hydrogen bond acceptor (HBA) features
and displayed the importance of these features toward the HDAC8
inhibitory activity of these compounds. The 3D-QSAR model
generated contours of the best and the least active compounds of
that dataset suggested that the HBD feature near the hydroxamate
nitrogen atom of the most active compound (83) is favouring its
activity whereas the HBD feature of the least active compound (84)
suggested the negative influence on its activity [Fig. 18(A)]. The
contours also suggested beneficial effects of bulky group substitu-
tion as the ring aromatic (RA) feature near the thiazole ring of the
most active compound. The presence of RA feature of the least
active molecule near its methoxy phenyl moiety suggested it to be
detrimental for its HDAC8 inhibition [156]. For the most active
compound, the thiazole moiety was also identified to provide
electron withdrawing effect, providing the positive influence
 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Fig. 19. Structure and 3D-QSAR generated pharmacophore pheactures of compound
87.
toward its HDAC8 inhibitory activity but the carboxyl group in its
structure with its electron withdrawing effect seemed to be influ-
encing negatively towards its activity.
On the basis of pharmacophore based 3D-QSAR model and
docking results, two lead molecules DB08732 (85) and 15602 (86)
[Fig. 18(B)] were screened as hit molecules for HDAC8 inhibition
[156]. The ADMET, density function theory (DFT) and electrostatic
potential calculation study was also conducted on these molecules.
The ADMET study disclosed that these compounds (DB08732 and
15602) both posses drug like characteristics whereas the DFT and
electrostatic potential calculations exhibited the similarity of these
molecules with the FDA approved HDAC8 inhibitor vorinostat
(SAHA) on the basis of HOMO (Highest occupied molecular orbital)
and LOMO (Lowest occupied molecular orbital) energy, band en-
ergy gaps and molecular electrostatic potentials of these molecules.
These finally upheld DB08732 (85) and 15602 (86) as lead proto-
type molecules to design potent HDAC8 inhibitor [Fig. 18(B)] [156].
In order to identify novel HDAC8 inhibitors, Kim et al. [157]
employed the pharmacophore-based 3D-QSAR approach for the
Fig. 20. Structures of the molecules (88-90) screened by Kim and his co-workers (2018).
235
virtual screening of the promising compounds from a diverse set of
molecules. In this study, they generated a number of pharmaco-
phore hypothesis using different combinations of pharmacophoric
features on a training set of 16 compounds with higher to less
HDAC8 inhibitory activity. Among these models, the one
comprising one HBD and two RA features provided the best sta-
tistical outcome which is given in Fig. 19 along with a most active
compound (87) of that training set.
They also used the DFT based approaches along with the phar-
macophoric hypothesis to virtually screen the potential HDAC8
inhibitors from the set of molecules. In this process of screening,
only 193 drug like molecules were screened from 1,10,000 com-
pounds using the 3D-QSAR pharmacophore model and ADMET
study [157]. Then a docking study with the HDAC8 3D structure was
conducted on the 193 screened compounds. As a result only 11 lead
molecules were identified as promising for HDAC inhibition. Thus, a
DFT based HOMO-LOMO study was future conducted on the lead
molecules and finally three hit molecules KM055296 (88),
HTS10917 (89) and SPB02579 (90) were identified as promising
lead molecules for potent HDAC8 inhibition (Fig. 20) [157].
In a very recent study, Amin et al. [3] conducted a fragment
based Bayesian classification QSAR method on 852 HDAC8 in-
hibitors to identify the good and bad molecular fragments
responsible for imparting the activity. In this study, a total of 1266
molecules with HDAC8 inhibitory potency was obtained from the
binding databases and subjected to initial screening to eliminate
duplicate molecules as well as by applying Lipinski's rule of five
[158] and Veber's rules [159]. Finally, the remaining 852 molecules
were used to construct a QSAR model based on Naïve Bayes clas-
sifier modelling and Laplacian-corrected Bayesian classifier
modelling. 588 molecules were used as the training set and the rest
of the 264 molecules were used as the test set compounds to sta-
tistically validate the model. The study was also able to provide an
insight into the HDAC8 inhibitors to identify important molecular
fragments obtained from ECFP_6 fingerprints and physico-chemical
descriptors [3]. The outcome of the study revealed that either
hydroxamate or carboxamate group can act as the good ZBG than
the benzamide group for better HDAC8 inhibition. The study also
provided information about the surface recognition or cap group of
these molecules. It also indicated about a positive correlation be-
tween the hydrophobicity of the cap group with the HDAC8
inhibitory activity of the molecules [3]. The higher hydrophobic
236 S. Banerjee et al. / European Journal of Medicinal Chemistry 164 (2019) 214e240
Fig. 21. Schematic representation of the summary of the SAR and QSAR studies conducted on HDAC8 inhibitors.
groups such as biphenyl and phenyl imidazole derivated groups
were suggested to be preferable as cap group than less bulky phenyl
derivatives for higher HDAC8 inhibition of these molecules.
8. Future perspectives
Design and development of potential and selective HDAC8 in-
hibitors is an important and challenging task. Based on the three
crucial structural and pharmacophoric requirements (cap function,
linker feature and the zinc binding group), newer effective HDAC8
inhibitors may be designed. In a recent study, Amin and his co-
workers proposed a modified fish-like structural orchestration of
the pharmacophoric characters that probably enhance the HDAC8
inhibitory potential [1]. In some cases, spacially for the benzohy-
droxamate derivatives, the compounds were seemed to possess
promising affinity toward both HDAC6 and HDAC8 isoforms. So
designing of potent HDAC6/HDAC8 dual inhibitors is also plausible.
Apart from the hydroxamate ZBG, there is other non-hydroxamate
ZBGs (such as thiol, carboxylic acid, boronic acid, trifluoromethyl
ketone, oxime, hydroxypyridine thione, tropolone, b-lactam and
other kind of heterocyclic ZBGs) those may also coordinate with the
zinc ion to execute HDAC8 inhibition [160]. Therefore, work is
continuing for designing potential HDAC8 inhibitors comprising
such type of non-hydroxamate ZBGs [160]. Being a zinc-dependent
metalloenzyme, targeting the ZBG of HDAC8 inhibitors must be
optimized as an initial strategy for designing higher active in-
hibitors that have already been proposed. In the current scenario,
rational drug designing (RDD) and molecular modelling strategies
appeared to be effective tools for optimization as well as identifi-
cation of lead compounds for HDAC8 inhibitors. These various
computational approaches can also be productive to design and/or
identify lead molecules for dual inhibition of HDAC isoforms. An
overall summarized outcome of SAR and QSAR studies of all these
different HDAC8 inhibitors is also shown in Fig. 21.
Hence, apart from these, theoretical and hypothetical in-
terventions along with lots of experimental studies have to be
performed simultaneously to gather knowledge about the detail
enzyme-drug interaction mechanisms. Last but not the least, the
ligand-bound X-ray crystal structures of different HDAC8 inhibitors
also provides valuable insights about the binding mode of in-
teractions and the related chemical structures involved into these
mechanisms. These crucial ligand-binding interactions and the SAR
as well as molecular modelling studies in combination with
rigorous approaches, in a nutshell, should be effective to design
potential target-specific HDAC8 inhibitors as lead candidates in
future those may be used as effective HDAC8 inhibitors.
Conflicts of interest
The authors have no conflict of interests.
Acknowledgments
SB is grateful to the All India Council for Technical Education
(AICTE) New Delhi for awarding a fellowship. NA is thankful to
University Grants Commission (UGC), New Delhi, India for
providing Rajiv Gandhi National Fellowship (RGNF). SAA sincerely
acknowledge Jadavpur University, Kolkata for awarding Junior
Research Fellowship under State Government Fellowship Scheme
of Jadavpur University, Kolkata, India. TJ is thankful for the financial
support from UPE Phase II Program of UGC, New Delhi to Jadavpur
University, Kolkata, India. We also thank the support from
Department of Pharmaceutical Technology, Jadavpur University,
Kolkata, India for providing the research facilities.
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