3.3 Triple Action Antibacterial Hybrid Agents
91
case other possible variations with different ordering of A, B and C is assumed
and where dashed lines are used to indicate the possibility of a range of different
structural categories linking the recognition elements. For all these structural types,
the design needs to be such as to resist chemically- or enzymatically-based cleavage
so the compounds reach their target biological interaction sites intact.
Many structural design expressions are incorporated within each classification
type but by doing this it can be helpful in systematizing the structural variety and
highlighting gaps and areas for further development. For clarity the beginning of
each type is highlighted in bold together with the specification of the sub-section.
3.3.4.2 Type I. A---B---C
The two linking groups as represented by the dashed lines which characterize this
type i motif could include acyclic (linear or branched) groups with one or more atoms
and/or one or more cyclic groups having spirocyclic motifs. With this general type
i, the whole assemblage, or parts thereof, could also be intrinsic to one or more of
the ring systems, with up to three linking groups or units present. One expression
of this, for example, could involve A being joined to C by another linking group.
Incorporating such rings in the linkers offers the prospect of defined and different
relative spatial distributions of the A, B and C recognition patterns.
Further variation in the spirocyclic template architecture can be obtained through
a stereogenic element at the spiro centre which can also involve both carbon or other
atoms like a quaternary nitrogen. Additional expressions of spirocycles in triple
action hybrid design could include C, Si and B as the spiro atom or atoms thus giving
rise to neutral (C, Si) or charged (negative—B
− or positive—quaternary N
+ ) sites
together with the appropriate counterions. Also one could include the possibility
of betaine systems (B
− , quaternary N
+ ) in the spiro structural motif. The relative
rigidity of the rings can be controlled by ring size. The pharmacophoric groups
could be incorporated as substituents on (like a hydroxyl or amino group) or in the
rings (like a carbonyl group). To help with the spirocyclic design process, useful
parameters for desirable physicochemical properties and the molecular shape index
in the context of some spiro-heterocyclic systems have been outlined by King et al.
(2019).
Spirocyclic systems are an increasingly important part of modern drug discovery
(Zheng et al. 2014), including antibacterials as exemplified by the gyrase B inhibitor,
Zoliflodacin, which is in Phase 3 clinical trials for the treatment of infections caused
by drug resistant Neisseria gonorrheae (Bradford et al. 2020). Zoliflodacin contains
a spiropyrimidinetrione unit with carbon as the spirocentre atom. This unit has linked
lactam and imide features in the pyrimidine ring. In general design, the embedding of
a secondary lactam moiety in one or both of the spirocyclic rings is worth exploring
further as it offers other opportunities for target site interactions through hydrogen
bonding rather than the spirocycle being just a carbocyclic scaffold. Separating the
NH and carbonyl groups of the original lactam by the spirocentre carbon would
also give different opportunities for such interactions or for the attachment of other
91
case other possible variations with different ordering of A, B and C is assumed
and where dashed lines are used to indicate the possibility of a range of different
structural categories linking the recognition elements. For all these structural types,
the design needs to be such as to resist chemically- or enzymatically-based cleavage
so the compounds reach their target biological interaction sites intact.
Many structural design expressions are incorporated within each classification
type but by doing this it can be helpful in systematizing the structural variety and
highlighting gaps and areas for further development. For clarity the beginning of
each type is highlighted in bold together with the specification of the sub-section.
3.3.4.2 Type I. A---B---C
The two linking groups as represented by the dashed lines which characterize this
type i motif could include acyclic (linear or branched) groups with one or more atoms
and/or one or more cyclic groups having spirocyclic motifs. With this general type
i, the whole assemblage, or parts thereof, could also be intrinsic to one or more of
the ring systems, with up to three linking groups or units present. One expression
of this, for example, could involve A being joined to C by another linking group.
Incorporating such rings in the linkers offers the prospect of defined and different
relative spatial distributions of the A, B and C recognition patterns.
Further variation in the spirocyclic template architecture can be obtained through
a stereogenic element at the spiro centre which can also involve both carbon or other
atoms like a quaternary nitrogen. Additional expressions of spirocycles in triple
action hybrid design could include C, Si and B as the spiro atom or atoms thus giving
rise to neutral (C, Si) or charged (negative—B
− or positive—quaternary N
+ ) sites
together with the appropriate counterions. Also one could include the possibility
of betaine systems (B
− , quaternary N
+ ) in the spiro structural motif. The relative
rigidity of the rings can be controlled by ring size. The pharmacophoric groups
could be incorporated as substituents on (like a hydroxyl or amino group) or in the
rings (like a carbonyl group). To help with the spirocyclic design process, useful
parameters for desirable physicochemical properties and the molecular shape index
in the context of some spiro-heterocyclic systems have been outlined by King et al.
(2019).
Spirocyclic systems are an increasingly important part of modern drug discovery
(Zheng et al. 2014), including antibacterials as exemplified by the gyrase B inhibitor,
Zoliflodacin, which is in Phase 3 clinical trials for the treatment of infections caused
by drug resistant Neisseria gonorrheae (Bradford et al. 2020). Zoliflodacin contains
a spiropyrimidinetrione unit with carbon as the spirocentre atom. This unit has linked
lactam and imide features in the pyrimidine ring. In general design, the embedding of
a secondary lactam moiety in one or both of the spirocyclic rings is worth exploring
further as it offers other opportunities for target site interactions through hydrogen
bonding rather than the spirocycle being just a carbocyclic scaffold. Separating the
NH and carbonyl groups of the original lactam by the spirocentre carbon would
also give different opportunities for such interactions or for the attachment of other