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4.4.13.7 Molybdenum and its compounds
It has been reported that molybdenum complexes show an inhibitory effect similar to
ampicillin [81]. A number of cis-dichloro/dibromo dioxidobis (2-amino-6-substituted ben-
zothiazole) molybdenum(VI) complexes have shown inhibitory effects on P. aeruginosa,
S. aureus and K. pneumoniae.EvenagainstfungilikeA. flavus and A. niger,theyexhibit
inhibitory effects. Further, there are reports about antimicrobial activity comparable to
ampicillin and tetracycline. Isostructural 4,4ʹ-azopyridine (4,4ʹ-azpy) pillared binuclear
dioxomolybdenum(VI) complexes show such activities.
4.4.13.8 Gallium and its compounds
It is found that gallium is an iron mimetic metal, whereby Ga-protoporphyrin (Ga(III)-
(4-carboxyphenyl) porphyrin [ClGaTCCP]) is recognized by the cell as iron, so it is me-
tabolized via the same me chanism. This inhibits essential pathways of the bacterial
cells and disrupts cellular respiration by inducing ROS production. Gallium, after di-
gestion, disrupts vital cellular pat hways, which include the prevention of electron
transfer for ATP production by respiratory pathways, inhibiting enzymes that break
down Ga, obstructing nutrient/iron release and promoting starvation. Generally, limit-
ing cellular respiration damages cell DNA, leading to cell death.
4.4.13.9 Indium and its compounds
Although all indium compounds are regarded as highly toxic and indium is not widely
dispersed in the environment, insufficient data are available on its effect on human
health. Some of its derivatives have been reported to show antimicrobial activities.
For example, the antimicrobial activity of indium tin oxide (ITO) along with T
4
bacte-
riophage against E. coli has been reported. A single dose of immobilized bacterio-
phage is sufficient to reduce the further growth of the bacterial population. Except at
pH 5.0, where the bacterial growth was physiologically inhibited, all ITO/T
4
systems
maintain their antimicrobial activity [82].
4.4.13.10 Aluminum and its compounds
The synthesis and anti microbial activity of N
2
O
2
tetradentate Schiff-base ligand from
salicylaldehyde and o-pheny lene diamine [83]. Even alum inum oxide nanoparticles
synthesized from Colletotrichum sp. are reported to possess inhibitory activity against
Listeria monocytogenes, Salmonella typhi, Chromobacterium violaceum, Fusarium oxy-
sporum and Aspergillus flavus. Further, it has been found that the activity of many
antibiotics increases when these metal-based nanoparticles are combined.
4.4 Classification of metal-based drugs 71
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4.4.14 Miscellaneous complexes and application as drugs/medicine
Metal complexes discussed above and not included, but which are already in clinical
use, show the importance of this developing field of drug design. It is beyond the
scope of the pre sent chapter to include many possible candidates, yet an attempt is
made to include as many as possible. To provide a brief overview of this area, the
following table serves as a list of some complexes that are in use as drugs. Table 4.2
lists some of the complexes useful as medicine.
Tab. 4.2: List of some metal-based compounds/complexes useful as drugs.
S. no. Metal Compound/
complex
Use Comments/trade name References
.Li LiC
H
O
Good source of
antioxidants
Increases the GABA level by
reducing glutamate.
Camcolith, Cibalith-S, lithane
[]
Li
CO
Manic depression []
C
H
L
NO
Good source of
antioxidant
[]
. Fe [Fe(NO)(CN)
)]
Vasodilation Nipride for acute shock
No release
[]
. Ga Ga (NO
)
Hypercalcemia of
malignancy
Granite, possible anticancer
agent
[]
. Ag AgNO
Disinfectant for
neonatal conjunctivitis
and treatment of burns
Silvadene
Flamazine
. Ca Ca (Cur)
Antimicrobial []
. Sn Sn (Cur)
Antifungal Membrane disruption by
inhibiting ATPase activity
[]
. Au Acetylthioglucose
derivate
Rheumatoid arthritis Ridaura orally active []
. Bi Bi (sugar)
polymers
Antiulcer antacid Pepto
Bismol
Ranitidine
Bisutex
De-Nol
[]
. Hg Hg organic
compounds
Antibacterial antifungal Thimerosal mercurochrome []
72 Chapter 4 Metal complexes and their therapeutic applications
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4.4.15 Summary
In this chapter, a survey of a variety of biologically active inorganic compounds of
transition metals, in general, is presented. The aspect of their drug candidature and
the mechanism of their action, if known, is included with each of the metals or their
complexes. The demonstrated effects have also been described, and an attempt has
been made to outline a future course of action. It is apparent that if antibiotics are
considered, the demand for drug-resistant antibiotics is a great challenge, which war-
rants the strategy of using metal complexes and metals as prospective alternatives.
This includes anticancer compounds of platinum and other metals, which is an inter-
esting area of future research. The future of metal complexes thus seems extremely
bright vivid and hopefully, in the next few years, more metal complex-based com-
pounds will not only be synthesiz ed but will also be able to reach clinical trials and
finally be launched as drugs to serve humanity.
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Chapter 5
Hydroxytriazenes and their cobalt complexes
as candidates for theoretical drug designing
5.1 Introduction
Medicinal applications of hydroxytriazenes, a group of chelating agents well known
for their analytical applications, have recently been studied by the author and his co-
worker. An entire book has been published by the author on the medicinal applica-
tions of hydroxytriazenes and triazenes [1–8]. The present book is dedicated to the
medicinal applications of metal complexes, so it warrants the inclusion of recent ad-
vancements in metal complexes of cobalt used for theoretical drug design, obtaining
predictions by applying PASS, ADMET and docking as real-time models for the objec-
tive. In this chapter, theoretical or computer-aided drug design has been elucidated
using eight hydroxytriazenes and their respective cobalt complexes for their anti-
inflammatory properties.
The names diazohydroxy amines and triazene oxides have been given in the
chemistry of carbon compounds edited by Rodd [11]. However, 3-hydroxytriazene has
been the commonly used name for this series of compounds. The functional group for
these compounds is shown in Fig. 5.1.
Although this chapter deals with the theoretical outline of recent developments in drug
designing, it would be of utmost significance to understand how molecules, ligands and
their metal complexes can actually be used to apply this strategy. For this purpose,
some ligands that we have synthesized, along with their cobalt complexes, have been
taken as sample molecules. Hydroxytriazenes, as mentioned above, have shown poten-
tial as drug-like molecules, as evidenced by numerous studies done at the authors’ lab
and publications. Not only the compounds but also their metal complexes have shown
potential as biologically active and medicinally important compounds. Based on the sur-
vey, it is desirable that the medicinal potential of some complexes based on hydroxy-
triazenes is highlighted in the present chapter as a model for the theoretical designing
of drugs/drug candidates. The detailed chapter content includes cobalt complexes of the
following hydroxytriazenes. The hydroxytriazenes used for theoretical studies along
with their complexes have been shown in Figure 5.2.
R
1
N
N
N
R
2
OH
Fig. 5.1: Functional group of 3-hydroxytriazenes.
https://doi.org/10.1515/9783111426136-005
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The tools used for application to hydroxytriazenes and their cobalt complexes are
1. PASS
2. ADME
3. Docking
The details of each of the three tools have already been discussed in the preceding
chapters. In view of this, it is obvious for the reader to go through the earlier chapter
entirely dedicated to theoretical drug designing. However, here each of the studies
has been discussed to unders tand the application using hydroxytriazenes as model
Fig. 5.2: Hydroxytriazenes and their cobalt complexes used for theoretical drug design.
5.1 Introduction 79
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molecules and their cobalt complexes to see how a complete strategy is developed to
design a molecule for medicinal application purposes. Further, appropriate focus has
been given to detailed anti-inflammatory activity as it was found that the molecules
of this series have excellent to moderate anti-inflammatory activities. In this context,
it would be appropriate to mention that the chapter has been attempted to, in fact,
compare the drug-likeness of a series of hydroxytriazenes in comparison to their co-
balt complexes. The PASS is a tool that predicts activities for ligands only, and thus
complexes cannot be used for prediction. Thus, in the respective table, only probable
activities of used hydroxytriazenes further experimentally verified in our laboratory
are appended. Table 5.3 gives details of possible activities of some hydroxytriazenes.
It would be pertinent here to give brief details of the PASS method and terms used
[12, 13]. The terms used in the table are:
Pa – it defines the probability of being active. It predicts the chances that the com-
pound belongs to a subclass of active compounds, and it resembles the structure
of molecules which are the most typical in a subset of activities in a training set.
Pi – it is the probability of being inactive.
In general, compounds with Pa values of more than 0.3 (30%) can be expected to have
predicted activities, and those with Pa < 0.3 are likely not to have the predicted activi-
ties. This has been demonstrated using listed hydrox ytriazenes (Sectio n 5.3). In this
table compounds that have Pa > 0.3 are only induced since their probability values
have better chances if validated experimentally for a particular activity. It is further
important here to highlight that out of several activities predicted, focus has been
kept on anti-infla mmatory activity only. This is because when experimentally veri -
fied, this series as well as their cobalt complexes have shown excellent in vivo results.
The next part, molecular docking, has also thus been done fo r these compounds. In
summary, a complete model for theoretical drug designing has been described in this
chapter for cobalt-hydroxytriazene complexes.
5.2 Docking protocol
The cobalt metal-complexed triazenylbenzenesulfonamide derivative was subjected
to docking simulations using the docking module developed in MOE 2015.1001 (molec-
ular operating environment) [14] in order to identify a promising candidate. The X-
ray co-crystal str ucture of human pancreatic alpha-amylase (1B2Y), the C-terminal
subunit of human maltase-glucoamylase (3TOP), cyclooxygenase-2 (3LN1) and FAD-
dependent NAD(P)H oxidase (2CDU) was obtained using the protein data bank. This
structure was further utilized to examine the potential binding interaction and mech-
anistic inhibition of the cobalt metal-complexed triazenylbenzenesulfonamide deriva-
tive [15–18]. Figure 5.1 illustrates the chemical structures of compounds used for
docking investigation. The initial generation of the ligand molecule’s chemical struc-
80 Chapter 5 Hydroxytriazenes and their cobalt complexes as candidates
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