3.3 Triple Action Antibacterial Hybrid Agents
97
usually an artifact of isolation from plant sources (Grycová et al. 2007). Other
substituted berberines can also undergo this thermal demethylation process. The
demethylation can be accomplished by straightforward thermolysis (Lo et al. 2013)
providing a convenient hook for the attachment of further groups by reaction at the
9-OH site produced (Li et al. 2010). The 9-hydroxyl group can also possibly serve to
direct further nucleophilic attack, for example by boronic acids in a Petasis type reaction (Guerrera and Ryder 2016) (Guerrera and Ryder 2016), to afford 8-substituted
derivatives of the type shown in Fig. 3.22c and d. For systems of the latter type,
standard azide-based click chemistry (Thirumurugan et al. 2013) could then be used
to attach a unit with the recognition element C as in Fig. 3.22e.
While berberrubine itself displays only weak to very weak antibacterial activity
against the Gram-positives Micrococcus luteus (Kim et al. 2002) and Mycobacterium
smegmatis (Gharbo et al. 1973) greater potency through increased target interaction
possibilities may result from conversion of the phenolic hydroxyl group at C9 in both
compounds Fig. 3.22c and e to the fluorosulfate group using SuFEx click chemistry
(Liu et al. 2018). Toxicity considerations in the handling of the initially required
gaseous reagent for this reaction, sulfuryl fluoride, has been mitigated by the introduction of fluorosulfuryl imidazolium salts which are bench-stable and act as alternative donors of the ‘F–O 2 S
+ ’ unit. An excellent detailed review of SuFEx chemistry
and applications in late-stage functionalization strategies for bioactive compounds
has been published recently by Barrow et al. (2019). The introduced SO 2 F group is
also a useful handle to add other pharmacophores.
Another valuable reaction of berberine and congeners is the direct introduction of secondary amino functionality at the 9-position by an aromatic nucleophilic
displacement reaction with primary amines. Although yields were moderate in the
case of palmatine, the ease of the reaction is a positive attribute, and through this
route, a derivative was found with good anti-Helicobacter pylori activity, with this
possibly being mediated via inhibition of Helicobacter pylori urease (Fan et al. 2020).
This displacement reaction has also been applied to berberine to give the 9-amino
substituted derivatives (Naruto et al. 1976; Wang et al. 2018).
It is also relevant to note here that tetrahydroberberine derivatives obtained from
berberrubine and with different substituents at the 9- and 12-positions have antibacterial activity against both Gram-positive and Gram-negative pathogens, particularly
one derivative with a C9-benzyloxy group and an imino-1,3,4-triazolyl group at C12
(Fig. 3.23b). This derivative had in vitro MIC values of 2 μg mL
−1 and 8 μg mL
−1
against MRSA and Pseudomonas aeruginosa respectively (Duan et al. 2017). Dual
DNA-targeting was indicated. with the 1,3,4-triazole moiety present being involved
(on the basis of molecular modeling studies) but this ring might also facilitate interaction with other targets. The key intermediate in the synthesis of this triazole derivative
and congeners was the tetrahydroberberrubine-12-aldehyde (Fig. 3.23a), which was
accessible in turn from berberine chloride via a compact three step synthesis in
good overall yield. This aldehyde, plus the 9-phenolic hydroxyl group, provide good
opportunities for the elaboration of further pharmacophoric elements at these sites
with a view to designed multiply active antibacterials.
97
usually an artifact of isolation from plant sources (Grycová et al. 2007). Other
substituted berberines can also undergo this thermal demethylation process. The
demethylation can be accomplished by straightforward thermolysis (Lo et al. 2013)
providing a convenient hook for the attachment of further groups by reaction at the
9-OH site produced (Li et al. 2010). The 9-hydroxyl group can also possibly serve to
direct further nucleophilic attack, for example by boronic acids in a Petasis type reaction (Guerrera and Ryder 2016) (Guerrera and Ryder 2016), to afford 8-substituted
derivatives of the type shown in Fig. 3.22c and d. For systems of the latter type,
standard azide-based click chemistry (Thirumurugan et al. 2013) could then be used
to attach a unit with the recognition element C as in Fig. 3.22e.
While berberrubine itself displays only weak to very weak antibacterial activity
against the Gram-positives Micrococcus luteus (Kim et al. 2002) and Mycobacterium
smegmatis (Gharbo et al. 1973) greater potency through increased target interaction
possibilities may result from conversion of the phenolic hydroxyl group at C9 in both
compounds Fig. 3.22c and e to the fluorosulfate group using SuFEx click chemistry
(Liu et al. 2018). Toxicity considerations in the handling of the initially required
gaseous reagent for this reaction, sulfuryl fluoride, has been mitigated by the introduction of fluorosulfuryl imidazolium salts which are bench-stable and act as alternative donors of the ‘F–O 2 S
+ ’ unit. An excellent detailed review of SuFEx chemistry
and applications in late-stage functionalization strategies for bioactive compounds
has been published recently by Barrow et al. (2019). The introduced SO 2 F group is
also a useful handle to add other pharmacophores.
Another valuable reaction of berberine and congeners is the direct introduction of secondary amino functionality at the 9-position by an aromatic nucleophilic
displacement reaction with primary amines. Although yields were moderate in the
case of palmatine, the ease of the reaction is a positive attribute, and through this
route, a derivative was found with good anti-Helicobacter pylori activity, with this
possibly being mediated via inhibition of Helicobacter pylori urease (Fan et al. 2020).
This displacement reaction has also been applied to berberine to give the 9-amino
substituted derivatives (Naruto et al. 1976; Wang et al. 2018).
It is also relevant to note here that tetrahydroberberine derivatives obtained from
berberrubine and with different substituents at the 9- and 12-positions have antibacterial activity against both Gram-positive and Gram-negative pathogens, particularly
one derivative with a C9-benzyloxy group and an imino-1,3,4-triazolyl group at C12
(Fig. 3.23b). This derivative had in vitro MIC values of 2 μg mL
−1 and 8 μg mL
−1
against MRSA and Pseudomonas aeruginosa respectively (Duan et al. 2017). Dual
DNA-targeting was indicated. with the 1,3,4-triazole moiety present being involved
(on the basis of molecular modeling studies) but this ring might also facilitate interaction with other targets. The key intermediate in the synthesis of this triazole derivative
and congeners was the tetrahydroberberrubine-12-aldehyde (Fig. 3.23a), which was
accessible in turn from berberine chloride via a compact three step synthesis in
good overall yield. This aldehyde, plus the 9-phenolic hydroxyl group, provide good
opportunities for the elaboration of further pharmacophoric elements at these sites
with a view to designed multiply active antibacterials.