Article review presentation in class

1. Scaffold Hopping in Drug
Development
Aklilu Samuel
Department of Pharmacognosy and
Pharmaceutical Chemistry
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2. Introduction
Scaffold hopping
 It is a method of drug design by altering or
replacement of central core of known bioactive
lead molecule with structurally similar/dissimilar
(Langdon etal, 2010)
 The scaffold is sometimes directly involved in
binding;
 Therefore changing the scaffold could increase
the binding affinity, changing the scaffold can
also lead to improved drug-like properties.
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3. Introduction
 Scaffold concept widely applied to generate
analysis and compare core structure of active
compounds and analogue series
 Scaffolds are obtained from compound by
removal of substituent’s(R-group) while retaining
ring system and linker fragment between rings.
 Each ring containing compounds yield scaffold
and addition of ring to compound yield additional
scaffold (Bajorath, 2017).
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4. Figure 1 Dissection of a molecule according to Bemis and Murcko [4].
Diazepam contains three side chains and one framework with two ring
systems and a zero atom linker
Introduction
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5. Scaffold hopping methods
 Scaffold hopping known as lead hopping, which
is generally incorporate
o Ring opening or ring closure,
o Heterocycle replacement,
o Peptidomimetic and
o Shape/topology-based scaffold hopping
 This method starts with known active compound
and end with a novel chemotype
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6. Figure 2 Pharmacophore from different sources
Pharmacophore
 Molecular entities that interact with a specific target,
namely an enzyme, a receptor, or an ion channel.
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7. Method of scaffold hopping
 Method of scaffold hopping is also classified
depending on the degree of change associated
with the original parent molecule.
1º hop
 Minor modifications like replacing or swapping
carbon and heteroatoms in a backbone ring
 Replacing carbon, nitrogen, oxygen and sulfur
atoms in hetrocycle.
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8. 2º hop
 More extensive ring opening and closures.
 It manipulate the flexibility of molecule by
controlling the total number of free rotatable
bonds which results in flexibility of molecule and
membrane penetration and absorption
Method of scaffold hopping
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9. 3º hop
 Imbalance of biologically active endogenous
peptides, can cause different human diseases,
including diabetes, cancer.
 Replacement of peptide backbones with non-
peptic moieties
 Useful strategy to develop or design molecule
which mimic the structural feature of peptides
using active peptide conformation as templates
Method of scaffold hopping
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10. 4º hop
 Complete new chemical backbone that only
retains interactions.
 It is considered as virtual screening (VS) rather
than scaffold hopping.
 VS aims at whole molecules as a hits whereas
scaffold hopping focuses on discovering novel
core structure.
Method of scaffold hopping
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11. Example of successful scaffold hopping
 Compared to compound 9 and to the most active
derivative compound 2, molecule 4A has a higher total
polar surface area (TPSA) and comparable ClogP,
anticipating improved drug-like properties
Figure 4 Chemical structures of OASS inhibitors 1[14]
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12.  Isoindoline-1-one derivative targeting extracellullar
receptor kinase (ERK) was identified by structure
based scaffold hopping drug design after the
development of BVD-523 which is ATP competitive
ERK inhibitor
Figure 5: Structure-based design from 4-pyridone to isoindolin-1-one
[15].
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13.  Four novel structures which have high affinity for GAK were developed by scaffold
hopping from isothiazolo[4,3-b]pyridine (Figure 6), which serves as starting chemical
for the discovery of GAK inhibitors based on scaffold hopping
Figure 6: Four scaffolds (isothiazolo[3,4-b]pyrazine (a), pyrazolo[1,5-
a]pyrimidine (b), imidazo[4,5-b]pyridine (c) and quinazoline (d) from based on
an isothiazolo[4,3-b]pyridine skeleton by scaffold hopping approach [16].
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14.  Similarly by combining scaffold hopping with the 3D-QSAR model, three new
potent molecules which were able to interact with the binding site and inhibit
FABP4 were identified as lead molecules. This could be a useful starting
point for the design of other FABP4 inhibitors
Figure 7: Isothiazolo[4,3-b]pyridine derived FABP4 inhibitors
[17].
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15.  A novel series of 2-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)acetamide
derivatives was synthesized based on structure of gefitinib.
Biological screening results showed that benzo[4,5]imidazo[2,1-
b]thiazole derivatives can be potential candidates as novel potential
EGFR inhibitors in further research
Figure 8: Design of target compounds based on the structure
of gefitinib [18]
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16.  By cyclization of benzyl piperazines core benzene to indane
core by scaffold hopping a series of N-indanylbenzamide was
discovered as a novel RORγt inhibitors. More potent
compound 5c with S enantiomer was identified after
explanation of SAR on benzyl core, piperazine ring, aryl and
cyclopentyl
Figure 9: cyclization of benzyl piperazines core benzene to
indane core by scaffold hopping to discover novel
compound 5c [19].
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17.  Similarly replacing one or two pyrrole N’s of porphyrin with other
hetero atoms (figure 11) such as O, S, Se, Te, Si, P, and C; the
resulting class of porphyrinoids are known as heteroatom-containing
porphyrins or core-modified porphyrins and possess
physicochemical properties that are different from regular N4-
porphyrins
Figure 10: Heteroatom-Containing Porphyrin
Analogues by core replacementof scaffold hopping
approach [20].
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18.  The scaffold hopping from imidazo[1,2-b]pyridazine into
the 1H-pyrrolo[2,3-b]pyridine enabled an introduction of
substituents at the corresponding position; the amide
group substituent at the 3-position of the 1H-pyrrolo[2,3-
b]pyridine core dramatically improved the selectivity over
Trks
Figure 11: scaffold hopping from imidazo[1,2-b]pyridazine into the
1H-pyrrolo[2,3-b]pyridine [21]
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19.  Further scaffold hopping of isoxazole derivative 4 and optimization of its
pharmacokinetic profile led to the discovery of the orally bioavailable
compound 6v. Which shows Selective N-methyl-D-aspartate receptor
subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do
not cause side effects associated with non-selective N-methyl-D-aspartate
(NMDA) antagonists
Figure 12: Scaffold hopping of isoxazole derivative 4 and
optimization of its pharmacokinetic profile [22].
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20.  Structural optimization of thiophene[3,2-d]pyrimidine has
been focused on the center core of the lead guided by
scaffold hopping and crystal packing analysis to form
dihydrofuro[3,4-d]pyrimidine derivatives as novel HIV-1
NNRTIs. This has demonstrated not only significantly
improved drug resistance profiles but also enhanced
solubility and bioavailability
Figure 13: structural optimization of thiophene[3,2-d]pyrimidine via
scaffold hopping[23]
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21.  Using a scaffold-hopping approach, imidazo[1,2-a]pyridine
analogues of the ZSTK474 (benzimidazole) class of
phosphatidylinositol 3-kinase (PI3K) inhibitors have been
synthesized by using a heteroaryl Heck reaction procedure, involving
palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-
a]pyridines with chloro, iodo or trifluoromethanesulfonyl-oxy (trifloxy)
substituted 1,3,5-triazines or pyrimidines. The new compounds
maintain the PI3K isoform selectivity of their benzimidazole
analogues, but in general show less potency
Figure 14: Imidazo[1,2-a]pyridine analogues of the ZSTK474
(benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors
[24].
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22.  Scaffold hopping of tricyclic pyridines was performed by
replacing pyridine with isoxazole. Interestingly, the novel
tricyclic isoxazole derivatives were highly potent and
selective against Cryptococcus neoformans. Particularly,
compound 8a (Figure 15) showed potent
anticryptococcal activity against C. neoformans with
MIC80 value of 0.031 μg/mL, representing a promising
lead compound for the development of novel CM
therapeutic agents
Figure 15: Replacing pyridine with isoxazole by scaffold hopping to
synthesize tricyclic isoxazole derivatives [25].
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23. Summary
 In pharmaceutical industry the development of new
drug faces challenges caused by reduced output of
new medicine, drug price the situation need more
efficient way to develop drug.
 Scaffold hopping is one of the methods used to
develop drugs from natural products, natural
hormones or other drug through structural
modification.
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24. Thanks
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